British Journal of Radiology (2004) 77, 177-182
© 2004 British Institute of Radiology
doi: 10.1259/bjr/54028034
Clinical use of intensity-modulated radiotherapy: part II
M T Guerrero Urbano, MRCPI, FRCR and
C M Nutting, MRCP, FRCR, MD
Radiotherapy Department and Head and Neck Unit, Institute of Cancer Research and Royal Marsden NHS Trust, London and Surrey, UK
Correspondence: Dr C Nutting, Head and Neck Unit, Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, UK
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Abstract
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Intensity-modulated radiotherapy (IMRT) is a novel conformal radiotherapy technique which is gaining increasingly widespread use. This second clinical article aims to summarize the published data pertaining to prostate cancer, pelvic irradiation, gynaecological and breast cancer. Prostate cancer patients represent the largest group treated to date. The main indication has been radiation dose escalation within acceptable normal tissue late toxicity. Phase II data are promising, but no randomized clinical trial data are available to support its use. Pelvic IMRT aims to deliver radical radiation doses to pelvic lymph nodes while sparing the bowel and bladder. Indications for breast IMRT data are reviewed, and current data presented. Further data from randomized trials are required to confirm the anticipated benefits of IMRT in patients.
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Introduction
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Intensity-modulated radiotherapy (IMRT) is a novel conformal radiotherapy (CRT) technique that produces highly conformal dose distributions. The clinical applications include conformal avoidance strategies aimed at reducing the radiation dose to organs at risk (OR) and hence normal tissue radiation toxicity, or radiation dose escalation to tumours with the goal of increased tumour control. This second of two articles [1] presents the published clinical data on the treatment of prostate cancer, pelvic lymph node irradiation including gynaecological tumours and breast cancer.
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Urological malignancies
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Prostate cancer
Prostate cancer is currently the single most common tumour site treated with IMRT Worldwide. The treatment goals are increased tumour control through dose escalation, and reduced late radiation toxicity.
At Memorial Sloane Kettering Cancer Center, a Phase II dose escalation study has been underway. IMRT was initially used at this institution to boost prostate cancer treated with 3DCRT to 72 Gy in 40 fractions. An additional 9 Gy in 5 fractions were given with 6 inverse-planned intensity modulated beams using dynamic multileaf collimation (DMLC) [2]. Stein et al [3] evaluated the number of equispaced co-planar IMRT fields required to obtain an optimum treatment plan for prostate cancer and showed an increase in the number of fields with increased prescription dose, ranging from 3 fields for 70 Gy plans to 7 to 9 beams for 81 Gy plans. Burman [4] showed that using a five-field IMRT plan, good conformal dose distributions were obtained to deliver 81 Gy to the planning target volume (PTV), and that the dose to the bladder and rectum were kept within tolerance (Figure 1
). This group first reported the acute toxicity observed using IMRT [5] comparing 61 patients with clinical stage T1c–T3 N0 M0 prostate cancer treated with 3DCRT and 171 with IMRT to a prescribed dose of 81 Gy, between 1992 and 1998. Acute and late radiation-induced morbidity was evaluated in all patients and graded according to the Radiation Therapy Oncology Group (RTOG) toxicity scale. They reported a 2 year actuarial risk of grade 2 bleeding of 2% for IMRT and 10% for conventional 3DCRT (p<0.001). A further report showed a significant reduction in the incidence of late grade 2 rectal toxicity in the patients treated to 81 Gy with IMRT compared with 3DCRT (2% versus 14%) and suggested an improvement in 5 year actuarial prostate specific antigen (PSA) failure and positive biopsy rates with increasing dose [6]. The largest report of IMRT for prostate cancer was published from the same group in 2002 [7]. A total of 772 patients were reported (698 treated to 81 Gy and 74 treated to 86 Gy). The maximum RTOG acute rectal toxicity was grade 2 in 4.5%. Only one patient reported acute bladder toxicity grade 3 and 28% had grade 2. Late rectal toxicity was grade 2 in 1.5% patients and grade 3 in 0.1%. Late bladder toxicity was grade 2 in 9% and grade 3 in 0.5% patients. The 3 year actuarial PSA relapse-free survival rates for favourable, intermediate and unfavourable risk group patients were 92%, 86%, and 81%, respectively. This phase II data appears to show increased PSA control with increasing radiation dose compared with historical controls. However, during the time period of this study, there has been an improvement in the prognosis of prostate cancer patients in the USA [8], and this represents a potential bias in the interpretation of data based on historical controls without randomized controlled data.
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Figure 1. A dose distribution for the treatment of prostate cancer using a five-field technique. Colourwash: 95% green, 70% yellow, 50% orange, 20% dark blue.
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De Meerler et al [9] used segmented static beams to escalate the dose to the prostate while keeping the anterior rectal wall maximum dose at 72 Gy. They showed that a three-field solution (0, 116° and 244°) using a biological objective function based computer optimization provided a significant increase the ratio of predicted tumour control probability (TCP) over rectal normal tissue control probability (NTCP).
The Cleveland Clinic Foundation used the increased rectal sparing observed with IMRT to deliver a hypofractionated schedule (70 Gy in 28 daily fractions) prescribed to an isodose line ranging from 83% to 90%. Tight (4 mm posteriorly, 8 mm laterally and 5 mm in all other directions) clinical target volume (CTV) to PTV margins were used and a 7% actuarial rate of rectal bleeding at 18 months was reported [10]. This group reported a statistically significant improvement in biochemical relapse-free survival in 166 patients treated with IMRT (70 Gy in 28 fractions) versus 116 patients treated with 3DCRT (78 Gy in 39 fractions) (94% vs 88%, p=0.084, non-randomized comparison). Actuarial late rectal toxicity for the hypofractionated IMRT group was 5%.
Bastash et al [11] reported no increase in erectile dysfunction following post-operative IMRT in 18 patients who remained potent after nerve-sparing prostatectomy, having received a mean dose of 69.6 Gy to the prostate bed.
Pelvic lymph node irradiation for prostate cancer
IMRT was shown in planning studies to reduce the dose to the small bowel during pelvic irradiation. Nutting et al [12] showed a significant 50–75% reduction in the volume of bowel irradiated to more than 45 Gy with inverse planned 3 to 9 field IMRT. A 5–7 beam DMLC technique to treat pelvic nodes and prostate has been implemented at the Royal Marsden Hospital to treat patients within a Phase I dose escalation study (Figure 2) [13]. The first phase of the study involved delivery of 70 Gy to the prostate gland, 64 Gy to the seminal vesicles and 50 Gy to the pelvic nodes to 20 patients. To date 53 patients have been treated and the current dose level is to 60 Gy. No Grade 
3 late gastrointestinal complications have been recorded so far (Dr DP Dearnaley, personal communication).
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Figure 2. A dose distribution for the irradiation of pelvic lymph nodes (pink outline) and bowel (blue outline). 60 Gy (yellow colourwash) is delivered as a boost to an enlarged node thought to be a metastasis, the remainder of the nodes receive 55 Gy (orange colourwash).
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Advances in imaging modalities such as endorectal MRI and MR spectroscopy (MRS) have made it possible to identify foci of carcinoma within the prostate. Pickett et al [14] used IMRT to boost an intraprostatic lesion, defined by MRI+MRS, to 90 Gy using 2.25 Gy per fraction while the entire prostate was treated to 70 Gy at 1.8 Gy per fraction and not exceeding normal tissue tolerances. Because of differences in the dose per fraction the biologic advantages of this technique are likely to be even greater. Intraprostatic boost is now used clinically at the University of California [15]. In a modelling study, a simultaneous integrated boost technique was used to dose escalate intraprostatic tumour nodules to 90 Gy by Nutting et al [16]. Improvements in TCP to NTCP ratio were suggested, although it was noted that this was dependent on the position of the intraprostatic node in relation to the anterior rectal wall. This technique is now used at this institution to boost positive pelvic nodes in patients with prostate cancer who are at high risk of pelvic node involvement (>30% risk), or patients with small volume pelvic lymphadenopathy in the absence of distant metastases utilizes the abovementioned phase I study.
Bladder
Improved PTV dose homogeneity with a reduction in both the high and low dose areas and reduction in normal tissue Dmax and rectal dose has been shown, both with DMLC [17] and forward planned partially wedged lateral beams [18].
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Gynaecological malignancies
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Primary radiotherapy for gynaecological malignancies usually requires whole pelvis radiotherapy followed by brachytherapy, with small bowel, rectum and bladder being the main dose limiting structures. The use of concomitant chemotherapy in locally advanced cancer of the cervix, while improving survival, is also associated with increased morbidity. Radiotherapy to the whole pelvis is also required following surgery if there is a high risk of lymph node involvement, especially in uterine carcinoma.
Low et al [19] postulated that IMRT may replace high dose-rate brachytherapy using an immobilization device within the vagina. Portelance et al and Roeske et al [20, 21] have shown in planning studies that IMRT reduces the volume of small bowel irradiated to 45 Gy during whole pelvis radiotherapy (WPRT) both for cervical and uterine cancer. Portelance et al [20] studied 10 patients with cervical cancer, treating the uterus, cervix and pelvic and para-aortic nodes to 45 Gy in 25 fractions. They compared 4-, 7- and 9-field Corvus plans delivered by DMLC with a 4-field box technique and showed a 58–67% reduction in the volume of small bowel irradiated to more than 45 Gy with IMRT that increased with the number of fields, but not beyond 7 fields.
Roeske et al [21] reported similar results in 10 patients with cervical or uterine carcinoma, treating the proximal vagina, parametrial tissues, uterus and pelvic nodes to 45 Gy in 25 fractions. A 50% reduction in the volume of small bowel irradiated to more than 45 Gy was observed with a 9-field Corvus plan when compared with 4 field 3DCRT.
Mutic et al [22] used IMRT to escalate the dose to positive para-aortic lymph nodes identified by PET to 59.4 Gy, and to 50.4 Gy to the para-aortic area while treating the pelvis with conventional methods. Similar results were achieved with arc IMRT in Japan [23].
Hong et al [24] developed a technique to treat the whole abdomen with DMLC IMRT. Five 15 MV intensity modulated beams were designed to spare the kidneys and bone marrow resulting in a 60% reduction in the volume of pelvic bones receiving more than 21 Gy and the same level of kidney sparing when compared with a conventional anteroposterior (AP)/posteroanterior (PA) 6 MV treatment.
Early clinical experience in 40 patients with gynaecological malignancies who received whole pelvis irradiation with IMRT, and brachytherapy to the cervix, uterus or vaginal vault if necessary, showed excellent PTV coverage (98.1% of the PTV receiving the target dose, with a median of 9.8% and 0.2% receiving 110% and 115% of the prescription dose, respectively) and reduced acute Grade 2 RTOG gastrointestinal toxicity (60% vs 91%) (p=0.002) and similar acute genitourinary toxicity (p=0.22) when compared with a contemporary cohort of patients receiving whole pelvis radiotherapy within chemoradiation protocols [25, 26]. A reduction in haematological toxicity was also observed by this group, in the chemo-IMRT treated patients, when compared with standard treatment (31% vs 60% grade 2 or greater white blood cell toxicity). This was attributed to a significant reduction of bone marrow irradiated, particularly within the iliac crests [27].
Accurate delineation of the pelvic nodes is required for pelvic radiotherapy in these patients and guidelines for the target volume definition have been proposed by Chao et al [28] using lymphangiography to determine the greatest distance from lymph node to vessel and pelvic side wall as a guide to CTV definitions on CT.
IMRT has been shown to provide improved dose distributions (Figure 3) when treating the pelvic nodes in the setting of both uterine and cervical carcinoma, with a reduction in the volume of small bowel irradiated beyond 45 Gy. The data currently available does not allow separate conclusions with regards to uterine and cervical cancer and primary and post-operative treatments. Another issue is whether IMRT could be a substitute for brachytherapy. In our opinion this is unlikely as brachytherapy offers the advantage of organ immobilization and very conformal dose distributions with steep dose gradients, which, so far, have not been achieved with IMRT.
Grade 3/4 bowel toxicity following conventional radiotherapy is reportedly low, but Grade 1 and 2, with their potential impact in the patient's quality of life is most likely under-reported. IMRT has an important role to play in future clinical studies evaluating possible reductions in bowel toxicity and their impact on quality of life following whole pelvis radiotherapy.
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Upper gastrointestinal tumours
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Oesophagus
Nutting at al [29] found that a 9-field Corvus plan had no advantages over 3DCRT but that a 4-field plan reduced the mean lung dose from 11 Gy to 9.5 Gy (p=0.001).
Pancreas
Forward-planned and inverse-planned IMRT and proton therapy were evaluated in the treatment of pancreatic and biliary duct tumours by Zurlo et al [30]. Proton therapy was superior to both IMRT techniques in both PTV coverage and normal tissue sparing.
Landry et al [31] predicted a reduction in bowel complication probability for pancreatic tumours using inverse-planned IMRT designed to deliver 61.2 Gy to the gross tumour volume (GTV) and 45 Gy to the CTV. An attempt by Crane et al [32] to escalate both the radiation dose and gemcitabine dose using IMRT resulted in dose limiting toxicity in all 5 evaluated patients.
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Second malignancy with IMRT
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An important issue with IMRT treatment delivery is that it requires a substantial increase in monitor units per target dose, therefore possibly increasing the risk of secondary malignancies outside the treatment area. In addition, the use of multiple fields in IMRT increases the volume of tissue receiving a low dose of radiation. Dorr et al [33] suggested that the majority of secondary malignancies are seen within 2.5 cm inside to 5 cm outside the margin of the PTV. Verellen et al [34] calculated the estimated whole-body equivalent dose for IMRT (1969 mSv) and conventional (242 mSv) delivery of 70 Gy with 6 MV photons. Using the nominal probability coefficient for a lifetime risk of excess fatal cancer (recommended by the ICRP 60) they suggested an increase in the risk of secondary malignancies by a factor of 8. Hall [35] has suggested that IMRT will almost double the incidence of second malignancies, from about 1% with conventional radiotherapy to 1.75% for patients surviving 10 years.
Long-term follow up of patients currently treated with IMRT is essential to evaluate accurately the risk of second malignancies in this group.
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Breast cancer
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Post-operative radiotherapy in women with breast cancer has been shown to improve locoregional disease-free survival [36] and overall survival [37–39] in several series. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis [36] suggested that radiation improved breast cancer-specific mortality but this was offset by an increase in deaths from cardiovascular disease. This was not apparent in the first 9 years after treatment and this study included trials that used radiotherapy techniques and equipment considered suboptimal by today's standards. Further studies have failed to show conclusively a difference in cardiac-related mortality [40, 41], and no differences in cardiac mortality between right and left sided breast irradiation have, so far, been identified. However long term follow up is necessary to evaluate fully the risk of cardiac toxicity, as this risk increases with time, and new radiation techniques such as IMRT offer the potential to reduce dose delivered not only to the left ventricle, but also the lung.
Treatment to the whole breast with standard tangential fields produces rather inhomogeneous dose distributions due to the variations in thickness across the target volume, in particular in large breasted patients [42]. The underlying ribs, lung and apex of the left ventricle are in part included within the same isodose as the target volume and hot spots are often found in areas of reduced tissue thickness, such as the superior and inferior aspects of the chest wall included in the radiotherapy field. These dose inhomogeneities may lead to increased late skin toxicity (poor cosmesis, fibrosis, pain) and increased cardiac and lung morbidity.
The dosimetric advantages of IMRT have been evaluated in several planning studies. Evans et al [43, 44] described the use of portal imaging in determining the relative thickness of breast and lung followed by the design of an automatic dose calculation algorithm to determine the optimum beam profile that allowed delivery of intensity modulated beams, first with custom-made compensators, and then with static multileaf collimation (SMLC) [45, 46] (Figure 4). A 25% reduction in the dose encompassing 20% of the coronary artery region in left breast treatments, and a 42% reduction in the mean dose to the contralateral breast using DMLC was shown by Hong et al [47]. There was also a 30% reduction in the ipsilateral lung volume receiving more than the 46 Gy prescribed dose and improved homogeneity across the target volume, particularly in the superior and inferior regions of the breast. Li et al [48] used four intensity modulated photon beams combined with an electron field to show a reduction in the dose to the ipsilateral lung and heart. Several planning studies [49–51] have also shown these dosimetric advantages and Landau et al [52] showed improved cardiac sparing with IMRT. This is of importance when considering treatment of the internal mammary nodes, which has been shown to improve disease free survival in high risk patients [53]. Remouchamps et al [54] showed that a significant reduction in the V30 heart volume to 3.1% is possible, with 2 direct tangential IMRT fields, as well as a mean lung V20 to 15.2% using moderate deep inspiration breath hold using an active breathing control system when compared with free breathing. In post-mastectomy patients, Krueger [55] showed an increased volume of contralateral breast was treated and increased contralateral lung dose with IMRT. Hurkmans et al [56] showed a 50% reduction in the NTCP for late cardiac toxicity.
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Figure 4. Isodose comparisons between standard conventional radiotherapy and intensity-modulated radiotherapy (IMRT) for breast cancer. Image provided by the Breast Technology Group, Royal Marsden Hospital/ Institute of Cancer Research, Sutton, Surrey, UK.
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Vicini et al [57] reported 281 patients with early stage breast cancer treated with breast conserving surgery, followed by whole breast radiotherapy using SMLC IMRT with a median number of 6 SMLC segments required per patient. Good dose homogeneity was reported with a median volume of breast receiving >105% of the prescribed dose of 11%. 97% of patients experienced acute skin toxicity grades 1–2.
A randomized controlled trial of 300 patients comparing IMRT with standard wedged tangential fields finished recruitment in 2000 at The Institute of Cancer Research and Royal Marsden Hospital [58]. The primary endpoint is late toxicity, measured with external photographic review and clinical and patient assessment. An analysis of the positional distribution of dose showed doses above 105% of that prescribed in the upper or lower breast regions in only 4% of patients treated with IMRT versus over 70% of patients treated with standard techniques [59] (Figure 4
). This analysis will allow effective correlation of dosimetry and clinical effects.
IMRT has also been shown to reduce the volume of ipsilateral lung treated beyond 15 Gy in a patient with pectum excavatum, although this was associated with an increase in the volume of heart, spinal cord and contralateral breast and lung receiving low-dose irradiation [60].
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Conclusions
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IMRT dose distributions have been shown, for a number of tumour types, to offer potential improvements in clinical outcomes. Planning studies have demonstrated which tumour types have the largest potential gains and small clinical studies are beginning to report short-term outcome data from patients. Most of these reports are small Phase I or II trials where there has been no true comparison of IMRT with the conventional radiotherapy technique. There is a tendency in some health care systems to adopt IMRT as standard of care for some tumour types without full testing in controlled trials. It is the authors' views that IMRT delivery should remain in the context of clinical trials until such time as these improved dose distributions have proven clinical benefits for patients.
Received for publication October 2, 2003.
Accepted for publication December 1, 2003.
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Abstract
Introduction
