Coverage Policy Manual
Policy #: 2011071
Category: Radiology
Initiated: June 2011
Last Review: February 2019
  Intensity Modulated Radiation Therapy (IMRT), Anus, Anal Canal

Description:
Intensity Modulated Radiation Therapy (IMRT) is a technology for delivering highly conformal external beam radiation to solid tumors or a specific treatment area.  The radiation beams are customized for each patient, the treatment volume is well defined and the beam intensity is modulated (non-uniform).  The delivery of modulated radiation beams makes IMRT useful to irradiate complex targets positioned near, or immediately adjacent to, sensitive normal tissues (organs at risk).  This type of treatment plan requires three-dimensional image acquisition (e.g., CT, MRI, PET) prior to the treatment planning.  
 
There are various methods of IMRT delivery. The most common is the multi-leaf collimator 1) static (step and shoot) where leaves do not move when the beam is on and 2) dynamic (sliding window) where they move during treatment while the beam is on.
 
IMRT results in a much sharper spatial dose gradient than conventional or 3D conformal radiation therapy.  Small changes in the patient or target position within the body (such as with respiration) can cause large changes in the dose delivered to the treatment volume and the organs at risk.  Immobilization of the patient and exact definition of the treatment volume is imperative.  
 
IMRT does not replace conventional or three-dimensional conformal radiation therapy.
 
For certain stages of many cancers, including breast, randomized clinical trials have shown that postoperative radiation therapy improves outcomes for operable patients.  IMRT is the subject of ongoing clinical trials of its use in whole breast or accelerated partial breast irradiation for women who have breast conserving surgery.  This can be done with conventional fractionation (lower dose in more treatment fractions) or with hypofractionation (higher dose in fewer treatment fractions).  
 
However, IMRT aims radiation at the treatment site from many more directions, and thus subjects more normal tissue to low-dose radiation than occurs with conventional EBRT or 3D-CRT. This may increase late effects of radiation therapy. In addition, since breast tumors move as patients breathe, dosimetry with stationary targets may not accurately reflect doses delivered within target volumes and adjacent tissues in patients. Furthermore, treatment planning and delivery are more complex, time consuming, and labor-intensive for IMRT than for 3D-CRT. Thus, clinical studies must test whether IMRT improves tumor control or reduces acute and late toxicities, when compared with 3D-CRT. Testing this hypothesis requires direct comparative data on outcomes for separate groups of similar patients treated with each method.
 
This policy was developed to address anal cancer specifically and was separated from the general IMRT policy in place since 2003, 2003015.
 
Related IMRT policies include:
2009036 Intensity Modulated Radiation Therapy (MRT)_Breast
2009035 Intensity Modulated Radiation Therapy (MRT)_Lung
2009034 Intensity Modulated Radiation Therapy (MRT)_Prostate
 

Policy/
Coverage:
Intensity modulated radiation therapy (IMRT) to treat squamous cell carcinoma of the anus/anal canal meets Primary Coverage Criteria.

Rationale:
Much of the reported literature describes case series.  Two of them describe results achieved with IMRT in patients with squamous cell carcinoma of the anal canal. The first is a single-institution series that included 17 patients with stage I/II cancer who underwent IMRT alone (n=3) or concurrent with 5-FU alone (n=1) or 5-FU with mitomycin C (MMC, n=13) (Milan0, 2005).  Patients generally received 45 Gy to the PTV at 1.8 Gy per fraction, followed by a 9 Gy boost to the gross tumor volume. Thirteen of 17 (76%) patients completed treatment as planned. None experienced acute or late grade 3 or above nonhematologic (GI or GU) toxicity. Grade 4 acute hematologic toxicity (leukopenia, neutropenia, thrombocytopenia) was reported in 5 of 13 (38%) patients who received concurrent chemoradiotherapy. At a median follow-up of 20.3 months, the 2-year OS rate was 91%.
 
A second multicenter series included a cohort of 53 consecutive patients who received concurrent chemotherapy and IMRT (Salama,2007).  Forty-eight (91%) received 5-FU plus MMC, the rest received other regimens not including MMC. Radiation was delivered at 45 Gy to the PTV. Thirty-one (58%) patients completed therapy as planned, with breaks in the others because of grade 4 hematologic toxicities (40% of patients), painful moist desquamation, or severe GI toxicities. At the18-month follow-up, the local tumor control rate was 83.9% (range: 69.9–91.6%), with an OS rate of 93.4% (range: 80.6–97.8%). Univariate analyses did not reveal any factors significantly associated with tumor control or survival rates, whereas a multivariate analysis showed patients with stage IIIB disease experienced a significantly lower colostomy-free survival (hazard ratio 4.18; 95% CI: 1.062–16.417; p=0.041).
 
The authors of these series suggest that their tumor control, survival, and toxicity results are similar to those achieved in earlier trials with concurrent chemoradiotherapy using non-IMRT methods.
 
Three case series reports were identified in the 2010 update. One was a gastrointestinal toxicity study in 45 patients who received concurrent chemotherapy and IMRT for anal cancer (Devisetty,  2009). Chemo-radiotherapy is becoming the standard treatment for anal cancer, in part due to preservation of sphincter function. Patients had T1 (n=1), T2 (n=24), T3 (n=16), and T4 (n=2) tumors; N stages included Nx (n=1), N0 (n=31), N1 (n=8), N2 (n=3), and N3 (n=2). Concurrent chemotherapy primarily comprised 5FU plus mitomycin C (MMC). IMRT was administered to a dose of 45 Gy in 1.8 Gy fractions, with areas of gross disease subsequently boosted with 9–14.4 Gy. Acute genitourinary toxicity was grade 0 in 25 (56%) cases, grade 1 in 10 (22%) patients, grade 2 in 5 (11%) patients, with no grade 3 or 4 toxicities reported; 5 (11%) patients had no genitourinary tract toxicities reported. Grades 3-4 leukopenia was reported in 26 (56%) cases, neutropenia in 14 (31%), and anemia in 4 (9%). Acute GI toxicity included grade 0 in 2 (4%) patients, grade 1 in 11 (24%), grade 2A in 25 (56%), grade 2B in 4 (95), grade 3 in 3 (7%) and no grade 4 toxicities. Univariate analysis of data from these patients suggests a statistical correlation between the volume of bowel that received 30 Gy or more of radiation and the risk for clinically significant (grade 2 or higher) GI toxicities.
 
Pepek et al. (2010) reported a retrospective analysis of toxicity and disease outcomes associated with IMRT in 47 patients with anal cancer.  Thirty-one patients had squamous cell carcinoma (SCC). Patients had AJCC stage I (n=6, 13%), stage II (n=16, 36%), stage III (n=14, 31%), stage IV (n=6, 13%), or recurrent disease (n=3, 7%). IMRT was prescribed to a dose of at least 54 Gy to areas of gross disease at 1.8 Gy per fraction. Forty patients (89%) received concurrent chemotherapy with a variety of agents including MMC, 5FU, capecitabine, oxaliplatin, etoposide, vincristine, doxorubicin, cyclophosphamide, and ifosfamide in various combinations. The 2-year actuarial OS for all patients was 85%. Eight patients (18%) required treatment breaks. Toxicities included grade 4 leukopenia (7%) and thrombocytopenia (2%); grade 3 leukopenia (18%) and anemia (4%); and, grade 2 skin (93%). These rates were much lower than previous trials of chemoradiation, where grade 3 to 4 skin toxicity was noted in about 50% of patients and grade 3 to 4 GI toxicity noted in about 35%. In addition, the rate of treatment breaks was lower than in many studies; and some studies of chemoradiation include a break from radiation therapy. Some investigators believe that treatment breaks reduce the efficacy of this combined approach.   The authors concluded IMRT is emerging as a standard therapy for anal cancer.
 
A small (n=6) case series of IMRT and concurrent infusional 5FU plus cisplatin in patients in patients with anal cancer with para-aortic nodal involvement was reported by Hodges et al. in 2009.  IMRT was delivered to a median dose of 57.5 Gy to the CTV, with nodal areas of involvement treated to a median dose of 55 Gy. Five of 6 completed the entire prescribed course of IMRT. The 3-year actuarial OS rate was 63%. Four patients developed grade 3 acute toxicities that included nausea and vomiting, diarrhea, dehydration, small bowel obstruction, neutropenia, anemia, and leukopenia. Five of 6 had grade 2 skin toxicity.
 
Bazan et al. reported a retrospective study, single center, 17 receiving conventional radiotherapy 1993-2002, compared to 29 receiving IMRT 2003-2009.  Each group received 54 Gy to the primary tumor and involved nodes.  Thirty-nine pts received concurrent 5FU & mitomycin C, 9 received 5FU & cisplatin.  The CRT group, compared to the IMRT group: required longer treatment duration – 57 vs 40 days; more treatment breaks – 88% vs 34.5 %; longer breaks – 12 vs 1.5 day; 65% experienced grade >2 nonhematologic toxicity vs 21%.  The 3-year overall survival (OS), locoregional control )LRC), and progression free survival (PFS) were 87.8%, 91.9% and 84.2% respectively for the IMRT group vs 51.8%, 56.7% and 56.7% for the CRT group.
 
DeFoe and colleagues report clinical outcomes in a group of 78 patients with anal cancer who received concurrent chemotherapy and IMRT at 13 community cancer centers.  All IMRT planning was done at one central location.  Median follow-up for the entire cohort was 16 mos (range 0-72 months).  Acute grade 3 toxicity occurred in 27.7% (GI) and 29.0% (dermatological).  Acute grade 4 hematological toxicity occurred in 12.9% of patients.  Sixty-four (88.9%) of patients experienced a complete response.  The 2-year colostomy free survival, overall survival, freedom from local failure, and freedom from distant failure rates were 82.1, 86.9, 83.6 and 81.8%, respectively.
 
October 2012 Update
No new randomized controlled trials were identified in a PubMed search through September 2012.  There were a few dosimetric comparison including an article by Brooks and colleagues in 2012.
 
There were reports of a few case series.  Call et al, 2011, did a retrospective review of 34 patients who received IMRT delivered to clinically negative nodal regions in patients receiving chemoradiotherapy for anal cancer.  Median follow-up duration was 22 months.  Three-year freedom from relapse was 80% and 3-year overall survival was 87% , estimated using Kaplan-Meier curves.
 
Kachnic et al., 2012, reported acute toxicity and response to therapy for 43 patients treated with dose-painted IMRT (DP-IMRT) and chemotherapy at two academic centers.  Median follow-up was 24 months. Sixty percent completed chemoradiation without interruption while median interruption for the others was 2 days (range 2-24 days).  Acute grade 3 toxicity included: hematologic 51%, dermatologic 10%, gastrointestinal 7% and genitourinary 7%.  Two-year local control, overall survival, colostomy-free survival, and metastasis-free survival were 95%, 94%, 90%, and 92%, respectively.
 
Vieillot et al., 2012, reported on the first 39 of 72 patients treated with IMRT, 1.8 Gy per fraction for 45 fractions, to the primary tumor and the risk area including pelvic and inguinal nodes.  A second plan delivered 1.8 – 2.0 Gy per fraction for a total of 14.4 – 20 Gy to the primary tumor.  Thirty-three of the patients also received chemotherapy.  Six patients required a treatment break of 3 days or longer with a median 8 day break.  Grade 3 gastrointestinal toxicity was seen in 10% of patients while 5% of patients had genitourinary toxicity.  Twelve percent of patients had grade 4 hematologic toxicity and those patients received CRT.  With 24-month follow-up there was no late grade 4 toxicity.  The 2-year overall survival, local relapse-free survival and colostomy-free survival was 89%, 77% and 85%, respectively.  
 
No changes are made to the coverage statement.
 
2013 Update
A search of the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
 
2014 Update
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A prospective cohort study was conducted by Han and colleagues to evaluate toxicity, quality of life (QOL), and clinical outcomes in patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for anal and perianal cancer (Han, 2014). From June 2008 to November 2010, patients with anal or perianal cancer treated with IMRT were eligible. Radiation dose was 27 Gy in 15 fractions to 36 Gy in 20 fractions for elective targets and 45 Gy in 25 fractions to 63 Gy in 35 fractions for gross targets using standardized, institutional guidelines, with no planned treatment breaks. The chemotherapy regimen was 5-fluorouracil and mitomycin C. Toxicity was graded with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. QOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR29 questionnaires. Correlations between dosimetric parameters and both physician-graded toxicities and patient-reported outcomes were evaluated by polyserial correlation. Fifty-eight patients were enrolled. The median follow-up time was 34 months; the median age was 56 years; 52% of patients were female; and 19% were human immunodeficiency virus-positive. Stage I, II, III, and IV disease was found in 9%, 57%, 26%, and 9% of patients, respectively. Twenty-six patients (45%) required a treatment break because of acute toxicity, mainly dermatitis (23/26). Acute grade 3 + toxicities included skin 46%, hematologic 38%, gastrointestinal 9%, and genitourinary 0. The 2-year overall survival (OS), disease-free survival (DFS), colostomy-free survival (CFS), and cumulative locoregional failure (LRF) rates were 90%, 77%, 84%, and 16%, respectively. The global QOL/health status, skin, defecation, and pain scores were significantly worse at the end of treatment than at baseline, but they returned to baseline 3 months after treatment. Social functioning and appetite scores were significantly better at 12 months than at baseline. Multiple dose-volume parameters correlated moderately with diarrhea, skin, and hematologic toxicity scores. IMRT reduces acute grade 3 + hematologic and gastrointestinal toxicities compared with reports from non-IMRT series, without compromising locoregional control. The reported QOL scores most relevant to acute toxicities returned to baseline by 3 months after treatment.
 
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Franco an d colleagues reported the 4-year outcomes of a consecutive series of anal cancer patients treated with concurrent chemo-radiation delivered with intensity-modulated radiotherapy (IMRT), employing a simultaneous integrated boost (SIB) approach (Franco, 2015). A consecutive series of 54 patients was enrolled between 2007 and 2013. Treatment schedule consisted of 50.4 Gy/28 fractions (1.8 Gy daily) to the gross tumor volume, while the elective nodal volumes were prescribed 42 Gy/28 fractions (1.5 Gy/daily) for patients having a cT2N0 disease. Patients with cT3-T4/N0-N3 tumors were prescribed 54 (T3) or 60 (T4) Gy/30 fractions (1.8-2 Gy daily) to the gross tumor volume; gross nodal volumes were prescribed 50.4 Gy/30 fr (1.68 Gy daily) if sized ≤ 3 cm or 54 Gy/30 fr (1.8 Gy daily) if > 3 cm; elective nodal regions were given 45 Gy/30 fractions (1.5 Gy daily). Chemotherapy was administered concurrently according to the Nigro's regimen. Primary endpoint was colostomy-free survival (CFS). Secondary endpoints were local control (LC), disease-free survival (DFS), cancer-specific survival (CSS), overall survival (OS), and toxicity profile. Median follow up was 32.6 months (range 12-84). The actuarial probability of being alive at 4 years without a colostomy (CFS) was 68.9% (95% CI: 50.3%-84.7%). Actuarial 4-year OS, CSS, DFS, and LC were 77.7% (95% CI: 60.7-88.1%), 81.5% (95% CI: 64%-91%), 65.5% (95% CI: 47.7%-78.5%), and 84.6% (95% CI: 71.6%-92%). Actuarial 4-year metastasis-free survival was 74.4% (95% CI: 55.5%-86.2%). Maximum detected acute toxicities were as follows: dermatologic -G3: 13%; GI-G3: 8%; GU-G3: 2%; anemia-G3: 2%; neutropenia-G3:11%; G4: 2%; thrombocytopenia- G3:2%. Four-year G2 chronic toxicity rates were 2.5% (95% CI: 3.6-16.4) for GU, 14.4% (95% CI: 7.1-28) for GI, 3.9% (95% CI: 1%-14.5%) for skin, and 4.2% (95% CI: 1.1-15.9) for genitalia.
 
2017 Update
A literature search conducted through February 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
A literature search conducted using the MEDLINE database through January 2018 did not reveal any new information that would prompt a change in the coverage statement.  
 
2019 Update
A literature search conducted using the MEDLINE database through February 2019 did not reveal any new information that would prompt a change in the coverage statement.  

CPT/HCPCS:
77301Intensity modulated radiotherapy plan, including dose-volume histograms for target and critical structure partial tolerance specifications
77338Multi-leaf collimator (MLC) device(s) for intensity modulated radiation therapy (IMRT), design and construction per IMRT plan
g6015Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session

References: Bazan JF, Hara W, et al.(2011) Intensity-modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal. Cancer, 2011; 117:3342-51.

Brooks CJ, Lee YK, et al.(2012) Organ-sparing intensity-modulated radiotherapy for anal cancer using the ACTII schedule: a comparison of conventional and intensity-modulated radiotherapy plans. Clin Oncol. 2012 Sep 14 [Epub ahead of print].

Call JA, Haddock MG, et al.(2011) Intensity-modulated radiotherapy for squamous cell carcinoma of the anal canal: efficacy of a low daily dose to clinically negative regions. Radiat Oncol, 2011; 6:134.

Defoe SG, Beriwal S, et al.(2011) Concurrent chemotherapy and intensity-modulated radiation therapy for anal carcinoma - clinical outcomes in a large National Cancer Institute-designated integrated Cancer Centre Network. Clini Oncol, 2011; Nov 8 [Epub ahead of print].

Devisetty K, Mell LK, et al.(2009) A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy. Radiother Oncol, 2009; 93:298-301.

Franco P, Mistrangelo M, Arcadipane F, et al.(2015) Intensity-modulated radiation therapy with simultaneous integrated boost combined with concurrent chemotherapy for the treatment of anal cancer patients: 4-year results of a consecutive case series. Cancer Invest. 2015 Jul;33(6):259-66.

Han K, Cummings BJ, Lindsay P, et al.(2014) Prospective Evaluation of Acute Toxicity and Quality of Life After IMRT and Concurrent Chemotherapy for Anal Canal and Perianal Cancer. Int J Radiat Oncol Biol Phys. 2014 Nov 1;90(3):587-94. doi: 10.1016/j.ijrobp.2014.06.061. Epub 2014 Sep 3

Hodges JC, Das P, et al.(2009) Intensity-modulated radiation therapy for the treatment of squamous cell anal cancer with para-aortic nodal involvement. Int J Radiat Oncol, Biol Phys, 2009; 75:791-4.

Kachnic LA, Tsai HK, et al.(2012) Dose-painted intensity-modulated radiation therapy for anal cancer: a multi-institutional report of acuted toxicity and response to therapy. Int J Radiat Oncol Biol Phys, 2012; 82:153-8.

Milano MT, Jani AB, et al.(2005) Intensity-modulated radiation therapy (IMRT) in the treatment of anal cancer: toxicity and clinical outcome. Int J Radiat Oncol Biol Phys, 2005; 63:354-61.

Pepek JM, Willett CG, et al.(2010) Intensity-modulated radiation therapy for anal malignancies: a preliminary toxicity and disease outcomes analysis. Int J Radiat Oncol Biol Phys, 2010; 78:1413.

Salama JK, Mell LK, et al.(2007) Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: a multicenter experience. J Clin Oncol, 2007; 25:4581-8.

Vieillot S, Fenoglietto P, et al.(2012) IMRT for locally advanced anal cancer: clinical experience of the Montpellier Cancer Center. Radiat Oncol, 2012; 7:45.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.