IMRT methods to plan and deliver radiation therapy are not uniform. (1-3) IMRT may use beams that remain “on” as MLCs move around the patient (dynamic MLC), or that are off during movement and turn on once the MLC reaches prespecified positions (“step and shoot” technique). A third alternative uses a very narrow single beam that moves spirally around the patient (tomotherapy). Each of these methods uses different computer algorithms to plan treatment and yields somewhat different dose distributions in and outside the target.
Patient position is another variable that can alter target shape and thus affect treatment plans. Some investigators and clinicians deliver 3D-CRT and IMRT with the patient prone, (4) while most treat supine patients as in conventional external-beam radiation therapy (EBRT). A recent comparative dosimetric analysis (published only as an abstract) concluded that target coverage is similar with either position, but plans generated for the prone position spared more lung tissue than those generated if the same patient was supine. (5) However, data are unavailable to compare clinical outcomes for patients treated in prone versus supine positions, and consensus is lacking.
Respiratory motion of the breast and internal organs (heart and lung) during radiation treatments is another concern when using 3D-CRT or IMRT to treat breast cancer. (6,7) Treatment plans are usually based on one scan, a static 3-dimensional image. They partially compensate for day-to-day (inter-fraction) variability in patient set-up, and for (intra-fraction) motion of the target and organs at risk, by expanding the target volume with uniform margins around the tumor (generally 0.5-1 cm for all positional uncertainty).
Current methods and ongoing investigations seek to reduce positional uncertainty for tumors and adjacent normal tissues by various techniques. Patient immobilization cradles and skin or bony markers are used to minimize day-to-day variability in patient positioning. Investigators are exploring an active breathing control device combined with moderately deep inspiration breath-holding techniques to improve conformality and dose distributions during IMRT for breast cancer. (6,7) Techniques presently being studied with other tumors (e.g., lung cancer ) either gate beam delivery to the patient’s respiratory movement or continuously monitor tumor (by in-room imaging) or marker (internal or surface) positions to aim radiation more accurately at the target. The impact of these techniques on outcomes of 3D-CRT or IMRT for breast cancer is unknown. However, it appears likely that respiratory motion alters the dose distributions actually delivered while treating patients from those predicted by plans based on static CT scans, or measured by dosimetry using stationary (non-breathing) targets. In addition, non-small cell lung cancer has more irregular, spiculated edges than many other tumors, including breast cancer. This precludes drawing tight margins on CT scan slices when radiation oncologists contour the tumor volume. It is unknown whether omitting some tumor cells or including some normal cells in the resulting target affects outcomes of 3D-CRT or IMRT. Another, more recent concern for highly conformal radiation therapy is the possibility that tumor size may change over the course of treatment as tumors respond or progress. Whether outcomes might be improved by repeating scans and modifying treatment plans accordingly (termed adaptive radiation therapy) is unknown.
These considerations emphasize the need to compare clinical outcomes rather than treatment plan predictions to determine whether one radiotherapy method is superior to another.
The literature search found no reports directly comparing health outcomes of IMRT with those of 3D-CRT for either breast or lung cancer treatment. There were no prospective comparative trials (randomized or nonrandomized). Since available data are scant, the Report summarizes the studies that reported health outcomes.
Kestin et al. reported they had treated 32 patients with early stage breast cancer using multiple static MLC segments to deliver IMRT for whole-breast irradiation. (9) With at least 1 month of follow-up on all patients, they observed no grade III or greater acute skin toxicity (using RTOG criteria). However, follow-up was inadequate to assess other health outcomes.
A subsequent report from Kestin and colleagues included 281 patients with early breast cancer treated with the same IMRT technique. (10) Of these, 102 (43%) experienced Radiation Therapy Oncology Group (RTOG) grade II, and 3 (1%) experienced grade III skin toxicity. Cosmetic results at 1 year after treatment were reported for 95 patients and were good to excellent in 94 (99%). No patients had skin telangiectasias, significant fibrosis, or persistent breast pain. Other primary or secondary outcomes were not reported.
Donovan et al. reported the treatment planning and dosimetry results from an ongoing randomized, controlled trial (RCT) comparing outcomes of radiation therapy for breast cancer using conventional EBRT with wedged, tangential beams or IMRT (n=300). (11) In an abstract, these investigators reported interim cosmetic outcomes at 2 years after randomization for 233 evaluable patients. (12) Changes in breast appearance were noted in 60 of 116 (52%) randomly assigned to conventional EBRT and in 42 of 117 (36%) randomly assigned to IMRT (p=0.05). Other outcomes were not reported.
IMRT has also been investigated as a technique of partial breast irradiation, as an alternative to whole-breast irradiation therapy after breast-conserving surgery. Breast brachytherapy (see policy No. 8.01.13) is another technique of partial breast irradiation therapy. A randomized intergroup trial that compared whole-breast and accelerated partial-breast irradiation, including IMRT, sponsored by the U.S. National Cancer Institute and led by the National Surgical Adjuvant Breast and Bowel Project and the Radiation Therapy Oncology Group opened in early 2005 (NSABP B-39/RTOG-0413). The trial is randomly assigning 3,000 patients to whole-breast or partial-breast irradiation after lumpectomy with tumor-free margins verified by histologic examination. The primary objective is to compare in-breast tumor control (i.e., recurrence rates) for whole-breast versus partial-breast irradiation. Investigators anticipate accrual will be completed by 29 months from the trial‘s start date. Lacking data with adequate follow-up from this or similar RCTs, there is inadequate published evidence to permit scientific conclusions about partial breast irradiation, regardless of whether it is delivered by IMRT or breast brachytherapy.
The literature search identified only 1 report on clinical outcomes of IMRT for patients with lung cancer. Holloway et al. reported on a Phase I dose escalation study that was terminated after the first 5 patients received 84 Gy in 35 fractions (2.4 Gy per fraction). (13) Treatment planning used combined CT and positron emission tomography for volumetric imaging, and treatment beams were gated to patients’ respiration. Acute toxicities included 1 patient with RTOG grade II dysphasia, 1 with grade I odynophagia, and 1 with grade I skin desquamation. In addition, 1 patient died of lung toxicity and was shown on autopsy to have bilateral diffuse pulmonary fibrosis with emphysema and diffuse alveolar damage. Of those who survived, 1 remained disease-free at 34 months, 2 developed metastases, and 1 developed an in-field recurrence.
The policy was updated based on a literature search through November 2006. No additional studies were found in the literature search that would change the conclusions of the policy statements above related to breast or lung cancer. These conclusions are based on the lack of studies with sufficient follow-up that compare IMRT to other forms of radiation therapy.
Some local medical review policies (LMRP), published by Medicare Part B carriers, have indicated that IMRT for the lung is considered medically necessary. These documents do not provide a detailed rationale for this conclusion.
The policy was updated with a literature search using MEDLINE in December 2007.
Lung Cancer No published trials were identified comparing IMRT with conventional approach. Thus the policy statement related to lung cancer remains unchanged.
Breast Cancer Donovan et al. reported on a trial from Britain of conventional 2D radiation therapy with IMRT in women with breast cancer (whole breast irradiation) who were treated between 1997 and 2000. (14) Three-hundred and six (306) women prescribed whole breast radiotherapy after tumor excision for early stage cancer were randomly assigned to 3D IMRT (test arm) or 2D radiotherapy delivered using standard wedge compensators (control arm). All patients were treated with 6 or 10 MV photons to a dose of 50 Gy in 25 fractions to 100% in 5 weeks followed by an electron boost to the tumor bed of 11.1 Gy in 5 fractions to 100%. The primary endpoint was change in breast appearance scored from serial photographs taken before radiotherapy and at 1, 2, and 5 years’ follow-up. Secondary endpoints included patient self-assessments of breast discomfort, breast hardness, quality of life, and physician assessments of breast induration. Two-hundred forty (79%) patients with 5-year photographs were available for analysis. Change in breast appearance was identified in 71/122 (58%) allocated standard 2D treatment compared to 47/118 (40%) patients allocated 3D IMRT. Significantly fewer patients in the 3D IMRT group developed palpable induration assessed clinically in the center of the breast, pectoral fold, inframammary fold and at the boost site. No significant differences between treatment groups were found in patient-reported breast discomfort, breast hardness or quality of life. The authors concluded that the analysis suggests that minimization of unwanted radiation dose inhomogeneity in the breast reduces late adverse effects. While the change in breast appearance was statistically different, a beneficial effect on quality of life was not demonstrated. Since whole breast radiation therapy is now delivered by 3D conformal techniques, these comparison data are of limited value. As the authors note, quality of life changes were not noted. No other clinical outcomes were reported. No other randomized trials comparing IMRT to standard radiotherapy were identified.
Most of the reports in the literature search described changes in radiation dose delivered for IMRT compared to other techniques. For example, Selvaraj reported on 20 patients with breast cancer randomly selected for comparison who received IMRT or 3D conformal radiation therapy (3D CRT). (15) In this study, the mean dose for the ipsilateral lung and the percentage of volume of contralateral volume lung receiving greater than 5% of prescribed dose with IMRT were reduced by 9.9% and 35% compared to 3D CRT. The authors note that the dosimetric data suggest improved dose homogeneity in the breast and reduction in the dose to lung and heart for IMRT treatments, which may be of clinical value in potentially contributing to improved cosmetic results and reduced late treatment-related toxicity. The literature review also identified pilot studies using IMRT for delivering accelerated partial breast irradiation. Leonard et al. reported on 55 patients treated with IMRT who had mean follow-up of 10 months. (16) At the short-term follow-up, the dose delivery and clinical outcomes were considered acceptable; however, comparative studies with long-term follow-up are needed.
The policy was updated with a literature search using MEDLINE through January 2009.
One additional RCT was identified; this was a comparison of IMRT to EBRT, and CT scans were used in treatment planning for both arms of the study. Thus, this is close to the ideal comparison of 3D-CRT and IMRT. Pignol and colleagues reported on a multicenter, double-blind, randomized clinical trial that was performed to determine if breast IMRT would reduce the rate of acute skin reaction (moist desquamation), decrease pain, and improve quality of life compared with radiotherapy using wedges. (17) Patients were assessed each week during and up to 6 weeks after radiotherapy. A total of 358 patients were randomly assigned between July 2003 and March 2005 in 2 Canadian centers, and 331 were included in the analysis. The authors noted that breast IMRT significantly improved the dose distribution compared with EBRT. They also noted a lower proportion of patients with moist desquamation during or up to 6 weeks after their radiation treatment; 31% with IMRT compared with 48% with standard treatment (p=0.002). A multivariate analysis found the use of breast IMRT and smaller breast size were significantly associated with a decreased risk of moist desquamation. The use of IMRT did not correlate with pain and quality of life, but the presence of moist desquamation did significantly correlate with pain and a reduced quality of life. The focus on short-term outcomes (6 weeks) is a limitation when assessing net health outcome.
McDonald et al. reported on a retrospective review of patients at one institution with Stages 0-III breast cancer who underwent irradiation after conservative surgery from January 1999 to December 2003. (18) Computed tomography simulation was used to design standard tangential breast fields with enhanced dynamic wedges for external-beam radiation therapy and both enhanced dynamic wedges and dynamic multileaf collimators for IMRT. In this report, 121 breasts were treated with IMRT and 124 with EBRT. Median breast dose was 50 Gy in both groups. Median follow-ups were 6.3 years for patients treated with IMRT and 7.5 years for those treated with EBRT. Treatment with IMRT decreased acute skin toxicity of RTOG Grade II or III compared with EBRT (39% vs. 52%, respectively; p=0.047). For patients with Stages I-III (n=199), 7-year Kaplan-Meier freedom from ipsilateral breast tumor recurrence (IBTR), rates were 95% for IMRT and 90% for cRT (p=0.36). Comparing IMRT with EBRT, there were no statistically significant differences in overall survival (OS), disease-specific survival, or freedom from IBTR, contralateral breast tumor recurrence, distant metastasis, late toxicity, or second malignancies. Interpretation of this study is limited by its retrospective design and limited outcomes measures (no quality of life measures). Publications are reporting early results on use of IMRT as a technique for accelerated whole and partial breast irradiation.
As noted above, no randomized trials were identified that compared IMRT to 3D-CRT. Noting that the use of IMRT for inoperable non-small cell lung cancer (NSCLC) had not been well studied, Sura and colleagues reviewed their experience with IMRT for patients with inoperable NSCLC. (19) They reported a retrospective review of 55 patients with Stage I-IIIB inoperable NSCLC treated with IMRT between 2001 and 2005. The study endpoints were toxicity, local control, and overall survival. With a median follow-up of 26 months, the 2-year local control and overall survival rates for Stage I/II patients were 50% and 55%, respectively. For the Stage III patients, 2-year local control and overall survival rates were 58% and 58%, respectively, with a median survival time of 25 months. Six patients (11%) experienced grade 3 acute pulmonary toxicity; 2 patients (4%) had grade 3 or worse late treatment-related pulmonary toxicity. The authors concluded that these results were promising. Given the limited data related to outcomes and comparative studies, the policy statement related to IMRT for treatment of lung cancer is unchanged.
The policy was updated with a literature search using MEDLINE through March 2010.
No randomized trials comparing IMRT to 3D-CRT that report clinical outcomes have been published. Barnett and colleagues have published baseline characteristics and dosimetry results of a trial of IMRT for early breast cancer. (20) In this trial, 1,145 patients with early breast cancer were evaluated for EBRT. Twenty-nine percent had adequate dosimetry with standard radiotherapy. The other 815 patients were randomly assigned to receive either IMRT or EBRT. Subsequent publications will report on late toxicity and quality of life.
Two recent publications report findings from single institutions from patients who received IMRT compared to patients who received EBRT (nonrandomized studies). The grading of acute radiation dermatitis is relevant to these studies. Acute radiation dermatitis is graded on a scale of 0 to 5, with 0 as no change and 5 as death. Grade 2 is moderate erythema and patchy moist desquamation, mostly in skin folds; grade 3 is moist desquamation in other locations and bleeding with minor trauma.
Freedman and colleagues studied the time spent with radiation-induced dermatitis during a course of radiation therapy for women with breast cancer treated with conventional radiation therapy or IMRT. (21) For this study, the population consisted of 804 consecutive women with early stage breast cancer treated with breast-conserving surgery and radiation from 2001 to 2006. All patients were treated with whole-breast radiation followed by a boost to the tumor bed. Whole-breast radiation consisted of conventional wedged photon tangents (n=405) earlier in the study period, and mostly of photon IMRT (n=399) in later years. All patients had acute dermatitis graded each week of treatment. The breakdown of cases of maximum toxicity by technique was as follows: 48%, grade 0/1, and 52%, grade 2/3, for IMRT; and 25%, grade 0/1, and 75%, grade 2/3, for conventional radiation therapy (p<0.0001). The IMRT patients spent 82% of weeks during treatment with grade 0/1 dermatitis and 18% with grade 2/3 dermatitis, compared with 29% and 71% of patients, respectively, treated with conventional radiation (p<0.0001). From this pre/post study, the authors concluded that breast IMRT is associated with a significant decrease both in the time spent during treatment with grade 2/3 dermatitis and in the maximum severity of dermatitis compared with that associated with conventional radiation. Interpretation of these results is limited by lack of a contemporaneous comparison.
In an earlier, but similar report, McDonald and colleagues reported on findings related to use of IMRT in breast cancer. (18) The objective of this study was to evaluate the long-term outcomes of IMRT with a comparison cohort receiving conventional EBRT during the same period. A retrospective review identified patients with Stages 0-III breast cancer who underwent radiation after conservative surgery from January 1999 to December 2003. Computed tomography simulation was used to design standard tangential breast fields with enhanced dynamic wedges for EBRT and both enhanced dynamic wedges and dynamic multileaf collimators for IMRT. Patients received a dose of 44–50.4 Gy to the whole breast in 1.8- to 2-Gy fractions, followed by an electron boost of 10–20 Gy. A total of 245 breasts were treated in 240 patients: 121 with IMRT and 124 with EBRT. Median breast dose was 50 Gy, and median total dose was 60 Gy in both groups. Median follow-up was 6.3 years (range: 3.7–104 months) for patients treated with IMRT and 7.5 years (range: 4.9–112 months) for those treated with EBRT. Treatment with IMRT decreased acute skin toxicity of RTOG grade II or III compared with EBRT (39% vs. 52%, respectively; p=0.047). For patients with Stages I-III (n=199), 7-year Kaplan-Meier freedom from IBTR rates were 95% for IMRT and 90% for EBRT (p=0.36). For patients with stage 0 (ductal carcinoma in situ, n=46), 7-year freedom from IBTR rates were 92% for IMRT and 81% for EBRT (p=0.29). Comparing IMRT with EBRT, there were no statistically significant differences in overall survival, disease-specific survival, or freedom from IBTR, contralateral breast tumor recurrence, distant metastasis, late toxicity, or second malignancies. The authors concluded that patients treated with breast IMRT had decreased acute skin toxicity, and long-term follow-up showed excellent local control.
Publications also report on the potential ability of IMRT to reduce radiation to the heart (left ventricle) in patients with left-sided breast cancer and unfavorable cardiac anatomy. (22) This is a concern because of the potential development of late cardiac complications, such as coronary artery disease, following radiation therapy to the left breast.
In summary, based on nonrandomized comparative studies, IMRT appears to produce clinical outcomes comparable to that of 3D-conformal radiation therapy. In addition, there is some decrease in acute skin toxicity with IMRT. However, whether there is an improvement in net health outcome compared to 3D-CRT is not known. Thus, since IMRT is generally more costly than 3D-CRT, yet produces similar outcomes, it is considered not medically necessary in the treatment of breast cancer.
Again, no randomized trials were identified that compared IMRT to 3D conformal radiation therapy (3D-CRT) in these patients with primary or metastatic disease.
Liao and colleagues report on a nonrandomized comparative study of patients who received one of these forms of radiation therapy, along with chemotherapy, for inoperable NSCLC at one institution. (23) This study involved a retrospective comparison of 318 patients who received CT/3D-CRT and chemotherapy from 1999–2004 (mean follow-up of 2.1 years) to 91 patients who received 4-dimensional computed tomography (4DCT)/IMRT and chemotherapy from 2004–2006 (mean follow-up of 1.3 years). Both groups received a median dose of 63 Gy. Disease endpoints were locoregional progression, distant metastasis, and overall survival (OS). Disease covariates were gross tumor volume (GTV), nodal status, and histology. The toxicity endpoint was grade III or greater radiation pneumonitis; toxicity covariates were GTV, smoking status, and dosimetric factors. Data were analyzed using Cox proportional hazards models. The hazard ratios for IMRT were less than 1 for all disease endpoints; the difference was significant only for OS. The median survival was 1.40 (standard deviation [SD]: 1.36) years for the IMRT group and 0.85 (SD: 0.53 years) for the 3D-CRT group. The toxicity rate was significantly lower in the IMRT group than in the 3D-CRT group. The V20 (volume of the lung receiving 20 Gy) was higher in the 3D-CRT group and was a factor in determining toxicity. Freedom from distant metastasis was nearly identical in both groups. The authors concluded that treatment with 4DCT/IMRT was at least as good as that with 3D-CRT in terms of the rates of freedom from local/regional progression and metastasis. This retrospective study found a significant reduction in toxicity and improvement in survival. The nonrandomized, retrospective aspects of this study from one center limit the ability to draw definitive conclusions from this report.
In summary, based on nonrandomized comparative studies, IMRT appears to produce clinical outcomes comparable to that of 3D-conformal radiation therapy. However, whether there is an improvement in net health outcome compared to 3D-CRT is not known. Thus, since IMRT is generally more costly than 3D-CRT, yet produces similar outcomes, it is considered not medically necessary in the treatment of lung cancer.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received from 1 physician specialty society and 2 academic medical centers (3 reviewers) while this policy was under review in 2010. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. Those providing input suggested that IMRT should be utilized in select patients with breast cancer (e.g., some cancers involving the left breast) and lung cancer (e.g., some large cancers).
Technology Assessments, Guidelines, and Position Statements
The current National Comprehensive Cancer Network (NCCN) guidelines for breast cancer indicate that uniform dose distribution is the objective and list various approaches to achieve this, including IMRT. (24)
The current NCCN guidelines for non-small cell lung cancer indicate that IMRT may be considered when a large volume of normal lung is being irradiated or when tumors are located close to critical structures, such as the spinal cord. (25)