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© 1999 AlphaMed Press
Intensity Modulated Radiation Therapy (IMRT): A New Promising Technology in Radiation Oncology
Department of Radiology/Radiation Oncology, Baylor College of Medicine, Houston, Texas, USA
Correspondence: E. Brian Butler, M.D., Baylor College of Medicine, One Baylor Plaza, 165B, Houston, Texas 77030-3498, USA. Telephone: 713-790-2637; Fax: 713-793-1300; e-mail: ebutler{at}onramp.net
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Abstract |
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 Top Abstract IntroductionIMRT--A Revolutionary ConceptConsiderations in the Delivery...Application of IMRT and...Clinical Outcome--The Baylor...The Cost of SMART...ConclusionReferences |
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Intensity modulated radiation therapy (IMRT) is a new technology in radiation oncology that delivers radiation more precisely to the tumor while relatively sparing the surrounding normal tissues. It also introduces new concepts of inverse planning and computer-controlled radiation deposition and normal tissue avoidance in contrast to the conventional trial-and-error approach. IMRT has wide application in most aspects of radiation oncology because of its ability to create multiple targets and multiple avoidance structures, to treat different targets simultaneously to different doses as well as to weight targets and avoidance structures according to their importance. By delivering radiation with greater precision, IMRT has been shown to minimize acute treatment-related morbidity, making dose escalation feasible which may ultimately improve local tumor control. IMRT has also introduced a new accelerated fractionation scheme known as SMART (simultaneous modulated accelerated radiation therapy) boost. By shortening the overall treatment time, SMART boost has the potential of improving tumor control in addition to offering patient convenience and cost savings.
Key Words. Intensity modulated radiation therapy • Conformal radiotherapy • SMART boost • Central nervous system tumor • Head and neck cancer • Prostate cancer • Reirradiation
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Introduction |
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TopAbstractIntroductionIMRT--A Revolutionary ConceptConsiderations in the Delivery...Application of IMRT and...Clinical Outcome--The Baylor...The Cost of SMART...ConclusionReferences |
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Together with surgery and chemotherapy, radiotherapy plays an important role in oncology, both in the definitive and palliative aspects of treatment. Three major aspects of radiation oncology are potentially important advances in cancer treatment. The first is a multidisciplinary therapeutic approach with important clinical applications, the second is the progress in the physics and dosimetry of radiotherapy that has clinical ramification, and the third is genetic radiotherapy that will be translated to clinical practice [1]. Intensity modulated radiation therapy (IMRT) is the product of advances in the technology of radiotherapy to deliver radiation more precisely to the tumor while relatively limiting dose to the surrounding normal tissues. The purpose of this paper is to discuss the new concept of IMRT, its application in radiation oncology and potential benefits over conventional radiotherapy.
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IMRT—A Revolutionary Concept |
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TopAbstractIntroductionIMRT--A Revolutionary ConceptConsiderations in the Delivery...Application of IMRT and...Clinical Outcome--The Baylor...The Cost of SMART...ConclusionReferences |
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In radiotherapy the single most important limiting factor is the normal tissue radiation tolerance, and the objective of optimal radiotherapy is to deliver the maximum radiation dose to the tumor while keeping the dose to the surrounding normal structures below tolerance [2]. To date this aim is achieved by the use of multiple treatment fields, choice of beam energies and modalities, weighting of different beams as well as the use of wedges and tissue compensators. In addition, two-dimensional customized blocks are routinely used to shield the normal structures. All of these conventional treatment-planning processes are approaches by trial and error. For example, a radiation oncologist will first place a radiation treatment field and then evaluate the dose. If the dose is not acceptable, a new field or other modification has to be made. This trial-and-error process has to be repeated until the optimal dose and coverage is achieved. This is time-consuming and sometimes no optimal plan can be reached.
IMRT combines two advanced concepts to deliver 3D conformal radiation therapy: A) inverse treatment planning with optimization by computer and B) computer-controlled intensity modulation of the radiation beam during treatment [3].
Inverse Treatment Planning with Computer Optimization
In contrast to the conventional trial-and-error approach, a radiation oncologist defines the tumor and the radiation dose that he wants around the tumor. The computer, using a mathematical optimization technique known as simulated annealing, will determine the optimal treatment fields. In addition, one can also define where one does not want the deposition of radiation (e.g., dose-limiting critical surrounding normal tissues). Figure 1
shows a smiling face demonstrating how radiation can be deposited in almost any pattern.
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Computer-Controlled Intensity Modulation of the Radiation Beam During Treatment
IMRT (NOMOS Peacock system; Sewickley, PA) has evolved from computer tomography (CT) concepts. A CT scan delivers uniform radiation exposure to the patient as it rotates around the patient's contour in a slice-by-slice fashion. Due to varying attenuation among multiple tissues, a nonuniform radiation dose exits the patient and hits the detector. The detector feeds this information to the computer, which processes it to create the sliced scan images. The Peacock IMRT system, on the other hand, starts with the target volume, where it places a uniform, conformal dose around the tumor. The computer then "backprojects" through the patient's tissue to the linear accelerator source and finds the nonuniform radiation exposure that must be delivered by the linear accelerator to give this conformal dose pattern. The system, like the CT scan, uses a slice-by-slice, arc-rotation approach. The concept of the Peacock system is demonstrated in Figure 2
.
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IMRT is a customized or individualized radiotherapy according to patient's location of tumor and anatomical structures, i.e., each patient has his or her own "unique" treatment plan. Blocks, compensators and wedges are obviated. With the availability of a powerful computer, planning time is short. Treatment delivery is also very efficient as there is no need for different energies of photons or mixed photon and electron beams. A special multileaf collimating system known as multileaf intensity modulating collimator (MIMiC) (Fig. 3
) is used to deliver spatially nonuniform radiation exposure to the patient to create a relatively uniform dose distribution at the target.
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Considerations in the Delivery of IMRT |
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TopAbstractIntroductionIMRT--A Revolutionary ConceptConsiderations in the Delivery...Application of IMRT and...Clinical Outcome--The Baylor...The Cost of SMART...ConclusionReferences |
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The more conformal a radiation treatment approach, the less error is allowed in patient set-up and treatment planning. In simpler terms, one cannot use conformal radiotherapy to treat a "moving target," as the incidence of "missing" the target is very high! Also, small movements can result in significant deviations from calculated doses based on an instantaneous image. Thus, patient and organ movements are of crucial concern when delivering conformal radiation therapy. The ideal site to start IMRT is the brain where the central nervous system (CNS) tumors are encased in the cranium. The only factor is patient's movement that can be minimized by either the Peacock "talon" system (invasive fixation device) or a special reinforced mask (noninvasive immobilization device). The talon system uses two self-tapping skull screws/sockets attached to the skull. The talon body is then secured to the screws/sockets. The body is then rigidly fixed to support the structure on the treatment table to achieve good patient immobilization [4].
In addition to the above immobilization techniques, an intraoral stent or bite-block is used for organ immobilization when treating head and neck cancers. Oral stents also serve the purpose of normal tissue avoidance, e.g., protecting oral tongue in treating the cancers of the hard palate.
Treating prostate cancers poses a challenge in both patient and organ movements. Due to anatomic and physical constraint, an invasive fixation technique for the pelvis was found not to be feasible. Prior experience with immobilization techniques enabled the development of a fiducial system linked to a treatment box. The patient lies prone in an evacuated beanbag that conforms both to the patient's body contour and the treatment box. Each patient has his own box with the fitted beanbag throughout the treatment. This has helped in solving the problem of patient movement.
The next problem is the previously well-documented movement of the prostate itself [5]. This problem is significant with regard to using IMRT to treat prostate cancer. Prostate motion during radiotherapy can lead to underdosing the target (prostate) and/or overdosing critical normal structures (rectum and bladder). A rectal catheter with an inflated balloon was developed to minimize the prostate motion. IMRT can then be delivered with more confidence. To date, only a limited attempt has been made to use IMRT in treating lung cancer, as it has proved difficult to immobilize lung and chest wall movement satisfactorily due to respiratory motion.
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Application of IMRT and its Potential Advantages |
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TopAbstractIntroductionIMRT--A Revolutionary ConceptConsiderations in the Delivery...Application of IMRT and...Clinical Outcome--The Baylor...The Cost of SMART...ConclusionReferences |
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Once the problem of patient and organ motion is resolved, IMRT can be applied to various tumors at various sites, either for definitive or palliative treatment intent.
To Create Multiple Targets
Multiple treatment targets can be created and treated at the same time. A good example is multiple brain metastases. For patients who have prior whole brain radiotherapy and need boost irradiation, or patients with metastatic radioresistant tumors, e.g., renal cell carcinoma or melanoma, multiple brain metastases can be treated simultaneously to high-dose radiation while other parts of the brain are avoided as shown in Figure 4. This has the benefit of decreasing treatment-related CNS toxicity.
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Besides creating multiple targets of the same origin, IMRT also enables the planning and treatment of multiple targets of different origins. A good example is in head and neck cancers as shown in Figure 5
. The primary target (red) includes all palpable and imaging documented abnormal tumor and lymph nodes. The secondary target (purple) includes all at-risk subclinical disease sites, e.g., all draining lymphatics, perineural routes, etc. Different targets can then be treated simultaneously with different fraction sizes and different total doses. This has significant implication in radiobiological control of gross versus subclinical disease. Another example is using IMRT to treat two completely unrelated tumors simultaneously as demonstrated in a patient with pituitary adenoma and chemodectoma (Fig. 6).
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To Create Multiple Critical Avoidance Normal Structures
There are many critical normal structures surrounding the targets, especially when treating head and neck or brain tumors. These structures include optic nerves and chiasm, lens, lacrimal glands, salivary glands, mandible, temporal lobes, brain stem and spinal cord. These structures usually have lower radiation tolerance, much lower than the tumoricidal radiation dose. Typical radiation thresholds used in these avoidance structures are shown in Table 1
. IMRT allows the creation of these avoidance structures on the treatment plan as well as the designation of their respective radiation thresholds. This has led to the concept of conformal avoidance, i.e., limiting the radiation to the surrounding structures below the designated threshold limit (Fig. 5
).
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Weightings
In addition to conformal treatment and avoidance, the Peacock IMRT system allows differential weightings on both targets and avoidance structures (Table 2
). Generally the target (tumor) is weighted more than the avoidance structures. However, in cases where a tumor surrounds a critical structure, e.g., optic chiasm, and the patient does not want to accept the treatment complication of losing his vision, the avoidance structure is then weighted more than the target. The ability of differential weighting has increased the versatility of IMRT and can be used to tailor to patient's needs and wishes.
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New Accelerated Fractionation Scheme
With the advent of IMRT and its capability to treat multiple targets simultaneously to different doses, a new accelerated fractionation scheme is introduced. It is known as simultaneous modulated accelerated radiation therapy (SMART) boost [4]. SMART boost can be applied to various sites including head and neck, brain and prostate. The principle is to treat two different targets with different fraction sizes to different total doses. A good example is the treatment of head and neck cancers. Accelerated repopulation of tumor clonogens during conventional fractionated radiotherapy has been recognized as an important cause of treatment failure in head and neck cancers, especially if the overall treatment time is prolonged. Both laboratory and clinical data [6-8] support this hypothesis. The reduction of overall treatment time has the potential for improving tumor control by minimizing tumor clonogen regeneration. Various purely accelerated treatment schedules have been used, e.g., Polish Trial (CAIR) [9], CHART [10], Massachusetts General Hospital accelerated split course [11] and M.D. Anderson Concomitant Boost [12] (Table 3
). These trials have suggested improved tumor control. By applying SMART boost by the use of IMRT, the primary target (palpable and imaging documented gross tumors and lymph nodes) and the secondary targets (at risk microscopic disease sites, e.g., draining lymphatics) are treated simultaneously to total doses of 60 Gy and 50 Gy, respectively over five weeks. Daily fraction sizes are 2.4 Gy and 2.0 Gy, respectively. As it is completed in five weeks compared to the conventional seven weeks, it is an accelerated scheme. SMART has the benefit of delivering only once-daily treatments, five days a week compared to other accelerated schemes usually involving twice or three-times-a-day or treating over the weekend. It is cost saving and offers patient convenience. More importantly, it has the radiobiological advantage of overcoming the accelerated repopulation of clonogens during radiation therapy that may lead to improved treatment outcome.
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Clinical Outcome—The Baylor College of Medicine Experience |
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TopAbstractIntroductionIMRT--A Revolutionary ConceptConsiderations in the Delivery...Application of IMRT and...Clinical Outcome--The Baylor...The Cost of SMART...ConclusionReferences |
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More than 700 patients have been treated with IMRT at the Baylor College of Medicine since March 1994 to date. Four major subsets were presented and discussed. These include: A) CNS; B) head and neck; C) prostate, and D) previously irradiated patients.
CNS
Both pediatric and adult benign and malignant brain tumors have been treated with IMRT. Table 4 shows various CNS tumors treated with IMRT.
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Eleven patients with medulloblastoma received IMRT as a posterior fossa boost after the initial craniospinal irradiation, while the remaining 68 patients were irradiated with IMRT for the full course. Total prescribed doses ranged from 36 Gy to 64 Gy. Noninvasive immobilization was used in 35 patients and invasive immobilization was used in the other 45 patients. Median follow-up was 24 months.
Figure 7 shows an axial plan of a patient with infratentorial ependymoma. The patient had gross total resection followed by full course IMRT. Temporal lobes and cranial nerve VIII are two important avoidance normal structures. With the capability of conformal avoidance by IMRT, the mean doses to temporal lobes and CN VIII are 21.7 Gy and 18.7 Gy, respectively, much below their tolerance threshold. Figure 8 shows an axial plan of a pituitary adenoma treated with IMRT. It illustrates the sparing of optic chiasm, temporal lobes, orbits and brain stem.
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Treatment-related toxicity was limited to mild headache in ten patients with two patients requiring steroids. Two patients with meningioma had symptoms from persistent peritumoral edema that was present before radiotherapy, requiring an increase in the steroid dose. Three patients had local scalp asymptomatic erythema. None of the patients with invasive immobilization developed any infection at local wound sites.
Two patients with optic nerve sheath meningioma have reported improvement in vision. Four patients (medulloblastoma, brain stem glioma, ganglioglioma and recurrent malignant meningioma) showed progression of disease. The remaining 76 patients (median follow-up of 30 months) showed no progression thus far.
Head and Neck Cancers
Twenty patients with primary head and neck cancers (Table 5) were treated with IMRT using the SMART boost technique with parotid preservation [4]. The treatment fields encompassed two simultaneous targets with primary target including palpable and imaging detected disease and secondary target including areas at risk for microscopic disease, e.g., lymphatic compartments. Daily fractions of 2.4 Gy and 2 Gy were prescribed to the primary and secondary targets to a total dose of 60 Gy and 50 Gy, respectively. The overall treatment course was over five weeks (daily treatment) rather than the usual seven weeks (daily treatment) or the more-than-daily treatment in other accelerated schemes. With the IMRT inverse planning system, we were able to limit the radiation dose to the parotid glands. For midline tumors the parotids were limited to 25 Gy. For a unilateral tumor the ipsilateral parotid was limited to 35 Gy and the contralateral gland to 25 Gy. Figure 5 shows an axial treatment plan of an oropharyngeal primary treated with SMART boost. It demonstrates two targets and sparing of parotid glands, mandible and spinal cord. Radiation Therapy Oncology Group (RTOG) acute toxicity grading criteria were used to evaluate surrounding normal tissue effects. Subjective salivary function was also assessed. Tumor response was evaluated by clinical examination, CT or magnetic resonance imaging (MRI) at periodic follow-up.
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Sixteen of 20 (80%) patients completed the treatment within 40 days. Two patients took up to 50 days to complete the treatment because of acute toxicity while two other patients completed the treatment in more than 50 days due to noncompliance rather than treatment-related side effects. Four separate organ systems were assessed using RTOG acute radiation morbidity scoring criteria [13]. Sixteen patients (80%) had RTOG grade 3 mucositis while ten patients (50%) had grade 3 pharyngitis. All patients recovered well after completion of radiotherapy. Encouragingly, more than half of the patients (55%) had grade 1 or less toxicity with the salivary gland; no patient had higher than grade 2 toxicity [4].
As xerostomia is a subjective report of symptom, the patients were asked to grade this symptom (none, mild, moderate and severe or complete). Eleven patients (55%) reported mild or no mouth dryness. Nine patients had moderate symptoms but none reported severe or complete xerostomia. Only one patient with moderate xerostomia was prescribed with pilocarpine. Time to relief of xerostomia varied from one to six months. A completely normal food intake was observed in seven patients.
Initial tumor response to SMART boost using IMRT is shown in Table 6. Nineteen patients (95%) had a complete response (CR) while one patient had a partial response (PR). Median follow-up was six months. Two of the 19 patients with local regional CR were found to have lung metastases at follow-up. There was no local regional recurrence or marginal miss.
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Prostate Cancer
Fifty men aged 56 to 82 with a mean of 70.8 years were included in the study. Clinical stages ranged from T1c to T3a. Median Gleason combined score was 6.5 (4-9). Mean pretreatment prostate-specific antigen (PSA) was 11.8 (3.6-60.0). All patients had negative metastatic work-up including chest x-ray, bone scan and CT of pelvis. Twenty-five (50%) patients had hormonal manipulation prior to and during radiotherapy. Patients treated with IMRT were prescribed a dose of 70 Gy in 35 fractions over 50-55 days. This is compared to the only randomized trial in this dose range, i.e., 70 Gy (conventional in 35 fractions over 50-55 days) and 78 Gy (six-field conformal in 39 fractions over 55-60 days) [14]. Patients were immobilized in a prone position in an evacuated "beanbag" contained in a box. Rectal balloon was used daily to minimize prostate movement. Patients treated with the conventional and six-field conformal radiotherapy were in supine treatment position without rectal balloon immobilization. The RTOG scoring system was used to assess acute toxicity. Median follow-up was 5.5 months (1 to 12 months).
Figure 9 shows an axial treatment plan of prostate cancer treated with IMRT. It illustrates well how use of the rectal balloon minimized the prostate motion as well as the highly conformal radiation dose coverage of tumor sparing the rectum. Mean doses to prostate, seminal vesicles, rectum and bladder were 75.8 Gy, 73.7 Gy, 34.2 Gy and 23.3 Gy, respectively. Although the prescribed dose for patients treated with IMRT was 70 Gy, the mean dose to the prostate was 75.8 Gy. There is dose inhomogeneity when the IMRT dosimetry is reviewed. At our institution we have used equivalent uniform dose (EUD) for reporting in order to give a more accurate delivered dose representation. EUD is found to be very similar to the mean dose in the treatment of prostate cancer. Thus, a higher dose is delivered with IMRT when compared to that of conventional treatment for prostate cancer despite the same prescribed dose. A mean dose of approximately 76 Gy over 35 fractions delivers a daily fraction size of approximately 2.17 Gy. Moderate dose escalation is desired as there is evidence to suggest dose response [15]. Higher radiation dose delivered with 3D conformal radiotherapy has been shown to improve treatment outcome of prostate cancer [15]. This is also a form of an accelerated fractionation scheme as 76 Gy is delivered over seven weeks in 35 fractions. The higher daily fraction size of 2.17 Gy is also well tolerated by patients as shown by the acute toxicity profile.
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Acute genitourinary (GU) and gastrointestinal (GI) toxicity are shown in Table 7
. There was a statistical difference (p < 0.001) for both GU and lower GI grade 0, 1, 2 toxicity between the IMRT and conventional or six-field conformal group. There was no grade 3 or higher toxicity noted in the IMRT group. Of note was the very low incidence of grade 2 GI toxicity in the IMRT group (14%) compared to the conventional (60%) and the six-field conformal group (66.7%) [16].
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It is too early to assess late toxicity or biochemical control (especially since 50% of the patients received androgen ablation). However, there already is an emerging trend suggesting that PSA nadir was reached early post-radiotherapy compared to nadir after conventional treatment. To date no patient has had a biochemical failure (three consecutive rises in PSA).
Recurrent Tumor Previously Irradiated
Ten patients with recurrent carcinoma in the head and neck were reirradiated to provide further local control as well as symptom palliation. Five patients had recurrent carcinoma of nasopharynx while the remaining consisted of recurrent carcinoma involving maxillary sinus, nasal cavity, medial canthus, oropharynx and posterior pharyngeal wall. All patients received prior radiotherapy ranging from 30 Gy to 67 Gy. They were all referred to our center as it was felt that no further radiation could be delivered safely to the local recurrence with conventional radiotherapy. Additional radiation was delivered with IMRT. The dose ranged from 16 Gy to 66 Gy. Toxicity was graded using RTOG morbidity scores, and tumor response was evaluated by clinical examination, CT and/or MRI. Follow-ups ranged from 2 to 12 months.
All patients were able to complete planned reirradiation at the scheduled time frame. There was no grade 3 or higher RTOG toxicity in mucosa, pharynx, skin or salivary glands that required split from treatment. All patients achieved the aim of palliation of local symptoms such as pain, epistaxis or discomfort. Quality of life has improved during and on completion of radiotherapy. Only half of the patients showed no progression of disease at the last follow-up.
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The Cost of SMART Boost |
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TopAbstractIntroductionIMRT--A Revolutionary ConceptConsiderations in the Delivery...Application of IMRT and...Clinical Outcome--The Baylor...The Cost of SMART...ConclusionReferences |
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Medicare allowable charge of SMART boost was compared to conventional fractionated radiotherapy and accelerated radiotherapy (concomitant boost) in the treatment of head and neck cancer as shown in Table 8
. This includes both professional and technical charges. Total Medicare allowable charge for SMART boost is $7,000 compared to $8,600 (conventional) and $9,400 (concomitant boost) [4].
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Conclusion |
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TopAbstractIntroductionIMRT--A Revolutionary ConceptConsiderations in the Delivery...Application of IMRT and...Clinical Outcome--The Baylor...The Cost of SMART...ConclusionReferences |
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Both theoretical and clinical data have shown the benefits of IMRT especially in decreasing acute treatment-related toxicity in either definitive or palliative reirradiated cases. This is made possible by delivering the radiation to the tumor with greater precision while relatively sparing the surrounding normal tissues. Minimizing toxicity is of major significance in all patients especially in treating childhood cancers. Quality of life is a very important issue for long-term survivors. Early tumor response and control are also very encouraging. With the lower treatment-related toxicity, dose escalation with IMRT is feasible in the future. This may have further implications for improvement of tumor control and cure. SMART boost with parotid preservation, a novel accelerated fractionation scheme with IMRT, is clinically feasible, radiobiologically beneficial and offers patient convenience. It is hoped to decrease the incidence of debilitating xerostomia and improve outcome of patients with head and neck cancers. Larger cohort and longer-term follow-up are warranted to demonstrate the impact of IMRT on improved tumor control and decreased long-term morbidity.
IMRT holds promise in radiation oncology in the new century. More clinical data are needed to confirm the potential promise.
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References |
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TopAbstractIntroductionIMRT--A Revolutionary ConceptConsiderations in the Delivery...Application of IMRT and...Clinical Outcome--The Baylor...The Cost of SMART...ConclusionReferences |
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