Medicine Section - Intensity Modulated Radiation Therapy (IMRT) of the Abdomen and Pelvis

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

DESCRIPTION

Intensity-modulated radiation therapy (IMRT) permits beam delivery with non-uniform cross-sectional intensity. This often relies on a device (a multi-leaf collimator, MLC) situated between the beam source and patient, that moves along an arc around the patient. As it moves, a computer varies aperture size independently and continuously for each leaf. Thus, MLCs divide beams into narrow “beamlets,” with intensities that range from zero to 100% of the incident beam. With an alternative, termed tomotherapy, a small radiation portal emitting a single narrow beam moves spirally around the patient, with intensity varying as it moves. Each method (MLC-based or tomotherapy) is coupled to a computer algorithm for “inverse” treatment planning. The planner/radiotherapist delineates the target on each slice of a CT scan, and specifies the target’s prescribed radiation dose, acceptable limits of dose heterogeneity within the target volume, adjacent normal tissue volumes to avoid, and acceptable dose limits within the normal tissues. Based on these parameters and a digitally-reconstructed radiographic image of the tumor and surrounding tissues and organs at risk, computer software optimizes the location and shape of beam ports, and beam and beamlet intensities, to achieve the treatment plan’s goals. Collectively, these methods are termed intensity-modulated radiation therapy (IMRT).

POLICY/CRITERIA

1. Intensity modulated radiation therapy (IMRT) may be considered medically necessary as a treatment for squamous cell cancer of the anal canal.
   
   
2. IMRT for other tumors of the abdomen or pelvis may be considered medically necessary when one or more of the following criteria are met:
   
   
   1. There is documented prior radiation treatment to the planned target area(s)
   2. A critical anatomical structure (spinal cord, heart, pancreas, kidney or small bowel) is located in the radiation field
   3. The organ targeted for treatment has documented significantly impaired function or limited capacity
      
      
3. IMRT for the treatment of all other abdominal or pelvic tumors is considered investigational.

SCIENTIFIC BACKGROUND ^[1]

General Information

Multiple studies have generated 3-dimensional conformal radiation therapy (3D-CRT) and IMRT treatment plans from the same scans, then compared predicted dose distributions within the target and in adjacent organs at risk. Results of such planning studies show that IMRT improves on 3D-CRT with respect to conformality to, and dose homogeneity within, the target. Dosimetry using stationary targets generally confirms these predictions. Thus, radiation oncologists hypothesized that IMRT may improve treatment outcomes compared with those of 3D-CRT by one or more of the following mechanisms:

• Increased conformality may permit escalated tumor doses without increasing normal tissue toxicity, and may thus improve local tumor control.
• Better dose homogeneity within the target may also improve local tumor control by avoiding underdosing (cold spots) within the tumor and may decrease toxicity by avoiding overdosing (hot spots).
• Finally, enhanced conformality for standard doses may reduce doses outside the target volume and thus decrease toxicity.

However, IMRT aims radiation at the tumor 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, because most 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.

Technology Assessments and Systematic Reviews

A systematic review published in 2008 summarized evidence on the use of IMRT for a number of cancers, including head and neck, prostate, gynecologic, breast, lung, and gastrointestinal. ^[2]  The authors presented the review as an analysis of comparative clinical studies; in reality, they categorized several small case series using historical cohorts as controls as comparative studies for several tumor types. This method limits the value of the review in assessing the role of IMRT for the diseases addressed in this policy.

Primary Literature

A literature search found no randomized controlled trials that compared health outcomes with IMRT versus those in patients treated concurrently with any other type of radiotherapy for tumors of the thorax (e.g., esophagus), upper abdomen (e.g., stomach, pancreas, bile duct, liver), or pelvis (e.g., rectal, anal, gynecologic). A few case series of IMRT were identified as well as a small number of non-randomized comparative studies with historical controls treated with non-IMRT methods.

Esophagus

• A small case series (n=30) reported the outcomes of patients with locally advanced esophageal cancer who received concurrent chemotherapy and IMRT (median follow-up of surviving patients = 24.2 months). ^[3] The actuarial local-regional control at 2 years was 83% for patients treated preoperatively vs. 51% for patients treated definitively. The overall survival (OS) at 2 years was 38% and 56% respectively. Twelve patients (40%) experienced grade 3+ acute complications and eight patients (27%) experienced grade 3 late complications. No grade 4 complications were observed. The study observed that disease recurrence remains a challenge and that further investigation is needed in order to improve LRC and OS.    

Gastric

As outlined in a recent review article, IMRT has been investigated for the treatment of gastric cancer in several studies.

• In a small (n=7) case series reporting clinical outcomes, patients with stage III gastric cancer received postoperative chemoradiotherapy with 5-fluorouracil (5-FU) and leucovorin and IMRT delivered to a dose of 50.4 Gy in 1.8 Gy fractions. ^[4] Chemoradiotherapy with IMRT was well tolerated, with no acute gastrointestinal (GI) tract toxicities (nausea, diarrhea, esophagitis) greater than grade 2.
  
  
• The efficacy and safety of two different adjuvant chemoradiotherapy regimens using 3D-CRT (n = 27) or IMRT (n = 33) were evaluated in two consecutive cohorts of patients who underwent primarily D2 resection for gastric cancer. ^[5] The cohorts in this study were generally well-matched, with American Joint Committee on Cancer (AJCC) advanced stage (II-IV) disease. The majority (n = 26, 96%) of those who received 3D-CRT were treated with 5-fluorouracil plus folinic acid (5FU/FA); the other patient received oxaliplatin plus capecitabine (XELOX). In the 3D-CRT cohort, 13 (50%) patients completed the 5FU/FA regimen, 13 halted early because of acute toxicity or progression, and received a median 60% of planned cycles. Patients in the IMRT cohort received XELOX (n = 23, 70%) or 5FU/FA (n = 10, 30%). Five of 10 (50%) patients completed all planned 5FU/FA cycles, the other 5 received only a median 60% of cycles because of acute toxicity. Thirteen (56%) treated with XELOX completed all planned cycles; the other 10 received a median of 70% planned cycles because of toxicity. Radiation was delivered to a total prescribed dose of 45 Gy/1.8 Gy/fraction in 21 (81%) of the 3D-CRT cohort patients; 5 received < 45 Gy because of intolerance to treatment. Thirty (91%) patients in the IMRT cohort received the planned 45 Gy dosage; 2 (6%) were unable to tolerate the full course, and 1 case planned for 50.4 Gy was halted at 47 Gy.
  
  The median overall survival (OS) was 18 months in the 3D-CRT cohort, and more than 70 months in the IMRT cohort (p = 0.0492). The actuarial 2-years OS rates were 67% in the IMRT cohort and 37% in the 3D-CRT group (p not reported). Acute renal toxicity based on creatinine levels was generally lower in the IMRT cohort compared to the 3D-CRT group, with a significant difference observed at 6 weeks (p = 0,0210). In the 3D-CRT group, LENT-SOMA grade 2 renal toxicity was observed in 2 patients (8%) whereas no grade 2 toxicity was reported in the IMRT group.
  
  The authors of this study assert that adjuvant IMRT with XELOX is more efficacious and associated with less renal toxicity than 3D-CRT with 5FU/FA in patients with advanced gastric cancer. However, the nonconcurrent cohorts study design precludes direct comparison of outcomes data and conclusions about the relative efficacy of these radiotherapy modalities in this setting.
  
  
• A small non-randomized study compared the clinical outcomes and toxicity in patients with gastric or gastroesophageal junction cancer who postoperatively received concurrent chemotherapy and either IMRT (n= 31) or 3D CRT (n=26). ^[6] Dose volume histogram parameters for kidney and liver were compared between treatment groups. The 2-year overall survival rates were not significantly different between the groups (51% for 3D CRT and 65% for IMRT). The groups experienced similar rates of locoregional failures (15% 3D CRT vs. 13% IMRT) and Grade ≥2 acute gastrointestinal toxicity (61.5 3D CRT vs. 61.2% IMRT); however, the 3D CRT group needed more treatment breaks (3 vs. 0). IMRT was found to provide sparing to the liver and possibly renal function.

The evidence from these studies is insufficient to draw conclusions about the efficacy and safety of IMRT for the treatment of gastric and esophageal cancers.

Hepatobiliary

• In a retrospective series with a historical control cohort, clinical results achieved with image-guided IMRT (n=24) were compared to results with CRT (n=24) in patients with primary adenocarcinoma of the biliary tract. ^[7] The majority of patients underwent postsurgical chemoradiotherapy with concurrent fluoropyrimidine-based regimens. IMRT treatment plans prescribed 46 to 56 Gy to the planning target volume (PTV) that includes the tumor and involved lymph nodes, in daily fractions of 1.8–2 Gy. CRT involved 3-D planning that delivered 46–50 Gy in 1.8–2 Gy daily fractions. Both groups received boost doses of 4–18 Gy as needed.
  
  The median estimated overall survival (OS) for all patients who completed treatment was 13.9 months (range: 9.0–17.6); the IMRT cohort had median OS of 17.6 months (range: 10.3–32.3), while the CRT cohort had a median OS of 9.0 months (range: 6.6–17.3). Acute GI toxicities were mild to moderate, with no significant differences between patient cohorts.
  
  These results suggest that moderate dose escalation via conformal radiotherapy is technically and clinically feasible for treatment of biliary tract adenocarcinoma. However, while this series represents the largest group of patients with this disease treated with IMRT, generalization of its results is limited by the small numbers of patients, use of retrospective chart-review data, nonrepresentative case spectrum (mostly advanced/metastatic disease), and comparison to a nonconcurrent control radiotherapy cohort
  
  
• A single arm study reported outcome with IMRT in 42 patients with advanced (33% AJCC stage IIIC, 67% stage IV) hepatocellular carcinoma (HCC) with multiple extrahepatic metastases. ^[8] Among the 42 cases, 33 (79%) had intrahepatic HCC with extrahepatic metastases, 9 (21%) had only extrahepatic lesions. The extrahepatic locations of HCC metastatic lesions included lung (n = 19), lymph node and adrenal (n = 20), other soft tissues (n = 6), and bone (n = 5). Helical tomotherapy was performed simultaneously for all lesions in each patient, with a total radiation dose of 50 and 40 Gy to 95% of the GTV and PTV in 10 fractions divided over 2 weeks. All received capecitabine during the course of IMRT as a radiosensitizer. After completion of tomotherapy, additional transarterial or systemic chemotherapy was administered to patients eligible for it according to tumor location. Among 31 patients who underwent hepatic IMRT, a mean of 3 courses (range 1-6) transarterial chemolipiodolization was performed in 23. Among 9 patients with extrahepatic lesions only, 3 received an additional 3-7 cycles of systemic chemotherapy consisting of epirubicin, cisplatin, and 5FU. Median follow-up was 9.4 months (range, 1.9-25.3 months).
  
  Tumor response was reported separately for each organ treated with IMRT. The overall objective tumor response rate was 45% for intrahepatic HCC, 68% for pulmonary lesions, 60% for lymph node and adrenal cases, and 67% for soft-tissue metastases. Three cases of local tumor progression occurred within the target radiation area, including 2 intrahepatic HCC and 1 abdominal lymph node metastasis. Median OS was 12.3 months, with 15% OS at 24 months. The most common acute adverse events were mild anorexia and constitutional symptoms that occurred 1-2 weeks after start of IMRT, regressed spontaneously or subsided with symptomatic care, and did not interfere with the scheduled delivery of IMRT. However, it is not possible to discern the impact of IMRT on adverse events because almost all occurred in patients who received chemotherapy following IMRT. Most patients were reported to have tolerated therapy well, with no treatment-related mortality.
  
  
• A second retrospective single-arm study involved 20 patients with primary, unresectable HCC who were treated with IMRT and concurrent capecitabine. ^[9] Patients had AJCC grade T1 (n = 7) and T3 (n = 13) HCC. IMRT was prescribed to a minimum tumor dose of 50 Gy in 20 fractions over 4 weeks, with the optimization goal of delivering the prescription dose to 95% of the PTV. Capecitabine was administered as radiosensitizer on the days of IMRT delivery. Eleven (55%) patients underwent at least 1 transarterial chemoembolization (range 1-3 procedures) before radiotherapy planning. Eighteen of 20 (90%) patients completed the full course of IMRT, 2 died before follow-up imaging was obtained. The mean survival of 18 patients who completed IMRT was 9.6 months after its conclusion. Disease progression occurred in-field in 3 patients, 2 failed elsewhere in the liver. Four patients (25%) required hospitalization during therapy, due to encephalopathy (n = 1), gastric ulcer (n = 1), acute hepatitis (n = 1) and sepsis (n = 1). Four required a break from chemotherapy because of peripheral neuropathy (n = 2), acute hepatitis (n = 1), and sepsis (n = 1). Grade 1 acute abdominal pain was observed in 15%, 30% reported grade 1 nausea, 5% experienced grade 2 nausea. No acute or late toxicity greater than grade 2 was reported.
  
  
• A small case series (n=40) reported the outcomes of irradiation dose escalation in patients with locally advanced hepatocellular carcinoma treated with a combination of 3D CRT/IMRT and transcatheter arterial chemoembolization. ^[10] The authors report that irradiation dose was safely escalated by using 3D/IMRT with an active breathing coordinator to a maximum tolerated dose of 62 Gy for patients with tumor diameters of <10 cm and 52 Gy for ≥10 cm. However, the findings are not reported for each radiation type separately.

The evidence from these studies is insufficient to draw conclusions about the efficacy and safety of IMRT for the treatment of HCC.

Pancreatic

The evidence on IMRT for the treatment of pancreatic cancer consists of a small number of case series and non-randomized comparative studies.  

• The largest series involved a retrospective analysis of 41 patients who received image-guided IMRT alone, postsurgically (41%), or with a number of concurrent primarily fluoropyrimidine-based chemotherapy regimens (88%). ^[11] The prescribed radiation dose to the PTV ranged from 41.4–60.4 Gy in daily fractions of 1.8–2 Gy. For all patients diagnosed with adenocarcinoma (85%), 1- and 2-year actuarial OS were 38% and 25%, respectively; median OS in resected patients was 10.8 months (range: 6.2–55.1), as compared to 10.0 months (range: 3.4–28.0) in inoperable cases. Four patients (9.7%) were unable to complete radiotherapy as prescribed. Any upper GI acute toxicity (none grade 4) was reported in 29 (70%) patients, most commonly nausea, vomiting, and abdominal pain; any lower GI acute toxicity (less than 5% grade 4) was reported in 17 (42%) cases, primarily diarrhea.
  
  
• In a series of 25 patients with pancreatic and bile duct cancers (68% unresectable), 24 were treated with IMRT and concurrent 5-FU, 1 refused chemotherapy. ^[12] Resected patients received 45–50.4 Gy to the PTV, whereas unresectable patients received 50.4–59.4 Gy. For all cancers, the median OS was 13.4 months, with 1- and 2-year OS of 55% and 22%, respectively. One- and 2-year median OS were 83% and 50%, respectively, among resected cases, and 40% and 8%, respectively, among unresected cases. IMRT was well tolerated, with grade 2 or less acute upper GI toxicity in 80% of patients; grade 4 late liver toxicity was reported in 1 patient who survived more than 5 years.
  
  
• A  retrospective series described  the experience of 15 patients with pancreatic adenocarcinoma (7 resected, 8 unresectable) who underwent IMRT plus concurrent capecitabine. ^[13] Resected cases received 45–54 Gy to the gross tumor volume, unresected cases received 54–55 Gy to the gross tumor volume; all cases received 45 Gy to the draining lymph node basin. At a median follow-up of 8.5 months, no deaths were reported among the resected patients, compared to 2 deaths in the unresected cases, yielding a 1-year OS rate of 69% among the latter. No grade 4 toxicities were reported, with the vast majority of acute toxicities reported at grade 1 (nausea, vomiting, diarrhea, neutropenia, anemia).
  
  
• A small non-randomized comparative study reported the difference in the rates of acute GI toxicity between pancreatic/ampullary cancer patients treated with concurrent chemotherapy and either IMRT or 3D CRT. ^[14] The design relied on historical controls. There was a significant decrease in upper and lower GI toxicity (nausea, vomiting, diarrhea) in the IMRT-treated group. There was no significant difference in grade 3-4 weight loss among two groups of patients.

The data from  the case series of IMRT for pancreatic cancer suggest that this technology may be safely used with concurrent chemotherapy in patients with resected or unresectable disease, producing mild to moderate toxicities primarily of the GI tract. However, given the limitations inherent in non-randomized and non-comparative designs, heterogeneity in terms of disease and use of concurrent therapies, small patient numbers, and a lack of direct comparative data, it is not possible to draw conclusions about the relative clinical efficacy or toxicities of IMRT versus any other radiotherapy method.

Gynecologic

• A series of reports from a single institution provided data on clinical outcomes achieved with IMRT in women with gynecologic malignancies. Patients from an initial series ^[15] were included in a subsequent report that comprised 40 patients who underwent IMRT to treat cancers of the cervix, endometrium, and other sites. ^[16] Patients in this series underwent postsurgical IMRT (70%), with (58%) or without (42%) cisplatin chemotherapy, with a majority (60%) also undergoing postradiotherapy intracavitary brachytherapy (ICB). IMRT was prescribed to the PTV at a dose of 45 Gy, delivered in 1.8 Gy daily fractions; ICB delivered an additional 30–40 Gy to cervical cancer patients and 20–25 Gy to those with endometrial cancer. A well-matched nonconcurrent cohort of patients who underwent 4-field CRT (45 Gy to the PTV, 1.8 Gy daily fractions) using 3D planning and received cisplatin chemotherapy was used to compare acute GI and genitourinary (GU) toxicities between radiotherapy modalities. No grade 3 acute GI or GU toxicities were reported in IMRT or CRT recipients. Grade 2 GI toxicity was noted in 60% of the IMRT cohort versus 91% of the CRT group (p=0.002). No significant differences were noted in the incidence of grade 2 GU toxicity in IMRT recipients (10%) compared to the CRT cohort (20%).
  
  Three other reports from the same group provide data on acute hematologic toxicity ^[17], chronic GI toxicities ^[18], and acute GI toxicities ^[19] among patients who underwent IMRT with or without chemotherapy. It is unclear whether or not the patients in these reports are those from the initial studies or are new patients.
  
  All of these studies uniformly suggest that the use of IMRT is associated with a low incidence of severe toxicities, although mild-to-moderate adverse effects were reported. However, no tumor control or survival data are available for comparison to CRT. Furthermore, generalization of these findings to current practice is limited by the small numbers of cases involved, the lack of concurrent controls, patient and treatment heterogeneities, and the relatively distant (1994-2002) timeframe during which they were accrued.
  
  
• Two subsequent studies examined the use of post-hysterectomy radiotherapy in women with high-risk cervical cancer. In the first study, 68 patients were treated with adjuvant pelvic radiotherapy, high dose-rate ICB, and concurrent chemotherapy. ^[20] The initial 35 cases received 4-field box CRT delivered to the whole pelvis; a subsequent 33 patients underwent IMRT. All patients received 50.4 Gy of radiation in 28 fractions and 6 Gy of high dose-rate vaginal cuff ICB in 3 insertions; cisplatin was administered concurrently to all patients. All patients completed the planned course of treatment. At median follow-up of 34.6 months (range: 12–52 months) in CRT recipients and 14 months (range: 6–25 months) in IMRT recipients, the 1-year locoregional control rate was 94% for CRT and 93% for IMRT. Grades 1 to 2 acute GI toxicities were noted in 36% and 80% of IMRT and CRT recipients, respectively (p=0.00012), while acute grade 1 to 2 GU toxicities occurred in 30% versus 60%, respectively (p=0.022). There was no significant difference between IMRT and CRT in the incidence of acute hematologic toxicities. Overall, the IMRT patients had lower rates of chronic GI (p=0.002) toxicities than the CRT patients.
  
  A subsequent report from the same group included the initial 33 patients in that experience with an additional 21 cases. ^[21] At a median follow-up of 20 months, this study showed a 3-year disease-free survival rate of 78% and an OS rate of 98% in IMRT recipients.
  
  
• A small case series involved 10 patients who underwent IMRT with intracavitary brachytherapy boost for locally advanced (FIGO stage IIB and IIIB) cervical cancer. ^[22] During radiotherapy, all patients received cisplatin. Whole pelvic IMRT was administered to a dose of 50.4 Gy in 28 fractions, and intracavitary brachytherapy was delivered to a dose of 30 Gy in 6 fractions. The mean OS was 25 months (range 3-27 months), with actuarial OS of 67%. Acute toxicities included 1 patient with grade 3 diarrhea, 1 with grade 3 thrombocytopenia, and 3 with grade 3 leukopenia. One case of subacute grade 3 thrombocytopenia was noted.
  
  
• Additional publications of IMRT for gynecologic cancer consist of small case series ^[23-26] and non-comparative ^[27] designs that continue to report favorable outcomes with IMRT treatment in patients with different types of gynecologic cancers (cervical, ovarian, endometrial). Generally the studies report favorable outcomes with IMRT treatment, but the need for large, prospective trials is also recognized in the literature.

These data are insufficient to draw conclusions about the efficacy or safety of IMRT in gynecologic cancers. While promising, the findings from these studies require confirmation in a randomized trial to rigorously compare the relative clinical outcomes achieved with IMRT and CRT in this disease setting.

Anorectal

• Two case series 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). ^[28] 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. ^[29] 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. However, they also acknowledge that their results are primarily hypothesis generating.
  
  
• One toxicity study reported outcomes in 45 patients who received concurrent chemotherapy and IMRT for anal cancer. ^[30] 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.
  
  
• Another report was a retrospective preliminary analysis of toxicity and disease outcomes associated with IMRT in 47 patients with anal cancer. ^[31] 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, adriamycin, cyclophosphamide, and ifosfamide in various combinations. The 2-years 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%), diarrhea (9%) and anemia (4%); and, grade 2 skin (93%), diarrhea (24%), and leukopenia (24%).
  
  
• Data was reported in another small (n = 6) case series of IMRT and concurrent infusional 5FU plus cisplatin in patients with anal cancer with para-aortic nodal involvement. ^[32] 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-years 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.
  
  
• Additional publications on IMRT for anorectal cancer include small case series ^[33-35] and non-randomized comparatives studies ^[36] that continue to report favorable outcomes and acceptable toxicity levels in IMRT treated patients.
  

Clinical Practice Guidelines

NCCN Guidelines vary for abdominal and pelvic cancers, depending on site:

Summary

The body of evidence available to assess the role of IMRT in the treatment of cancers of the upper abdomen and pelvis is comprised of several small case series (retrospective and prospective) and a small number of non-randomized comparative studies. No randomized trials have been reported that compared results with IMRT to any other CRT modality. The available results may be viewed as hypothesis-generating for the design and execution of comparative trials of IMRT versus CRT that evaluate tumor control and survival outcomes in the context of adverse events and safety.

While IMRT is considered a major advance in the delivery of radiotherapy, numerous potential pitfalls and hazards associated with this technology merit further examination. A recent review addresses these issues in the context of gynecologic cancers, and concludes that “IMRT gives an overstated impression of accuracy and precision of treatment delivery.” ^[48] The authors further assert that this has created a “tremendously false sense of security because the allure of precision from IMRT and inverse planning is at odds with the reality.” The review is written in the context of gynecologic cancers.

REFERENCES

1. BlueCross BlueShield Association Medical Policy Reference Manual "Intensity-Modulated Radiation Therapy (IMRT): Abdomen and Pelvis." Policy No. 8.01.49
2. Veldeman, L, Madani, I, Hulstaert, F, De Meerleer, G, Mareel, M, De Neve, W. Evidence behind use of intensity-modulated radiotherapy: a systematic review of comparative clinical studies. Lancet Oncol. 2008 Apr;9(4):367-75.  PMID: 18374290
3. La, TH, Minn, AY, Su, Z, et al. Multimodality treatment with intensity modulated radiation therapy for esophageal cancer. Dis Esophagus. 2010 May;23(4):300-8.  PMID: 19732129
4. Milano, MT, Garofalo, MC, Chmura, SJ, et al. Intensity-modulated radiation therapy in the treatment of gastric cancer: early clinical outcome and dosimetric comparison with conventional techniques. Br J Radiol. 2006 Jun;79(942):497-503.  PMID: 16714752
5. Boda-Heggemann, J, Hofheinz, RD, Weiss, C, et al. Combined adjuvant radiochemotherapy with IMRT/XELOX improves outcome with low renal toxicity in gastric cancer. Int J Radiat Oncol Biol Phys. 2009 Nov 15;75(4):1187-95.  PMID: 19409725
6. Minn, AY, Hsu, A, La, T, et al. Comparison of intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy as adjuvant therapy for gastric cancer. Cancer. 2010 Aug 15;116(16):3943-52.  PMID: 20564136
7. Fuller, CD, Dang, ND, Wang, SJ, et al. Image-guided intensity-modulated radiotherapy (IG-IMRT) for biliary adenocarcinomas: Initial clinical results. Radiother Oncol. 2009 Aug;92(2):249-54.  PMID: 19324442
8. Jang, JW, Kay, CS, You, CR, et al. Simultaneous multitarget irradiation using helical tomotherapy for advanced hepatocellular carcinoma with multiple extrahepatic metastases. Int J Radiat Oncol Biol Phys. 2009 Jun 1;74(2):412-8.  PMID: 18963538
9. McIntosh, A, Hagspiel, KD, Al-Osaimi, AM, et al. Accelerated treatment using intensity-modulated radiation therapy plus concurrent capecitabine for unresectable hepatocellular carcinoma. Cancer. 2009 Nov 1;115(21):5117-25.  PMID: 19642177
10. Ren, ZG, Zhao, JD, Gu, K, et al. Three-dimensional conformal radiation therapy and intensity-modulated radiation therapy combined with transcatheter arterial chemoembolization for locally advanced hepatocellular carcinoma: an irradiation dose escalation study. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):496-502.  PMID: 20421145
11. Fuss, M, Wong, A, Fuller, CD, Salter, BJ, Fuss, C, Thomas, CR. Image-guided intensity-modulated radiotherapy for pancreatic carcinoma. Gastrointest Cancer Res. 2007 Jan;1(1):2-11.  PMID: 19262697
12. Milano, MT, Chmura, SJ, Garofalo, MC, et al. Intensity-modulated radiotherapy in treatment of pancreatic and bile duct malignancies: toxicity and clinical outcome. Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):445-53.  PMID: 15145161
13. Ben-Josef, E, Shields, AF, Vaishampayan, U, et al. Intensity-modulated radiotherapy (IMRT) and concurrent capecitabine for pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):454-9.  PMID: 15145162
14. Yovino, S, Poppe, M, Jabbour, S, et al. Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):158-62.  PMID: 20399035
15. Mundt, AJ, Roeske, JC, Lujan, AE, et al. Initial clinical experience with intensity-modulated whole-pelvis radiation therapy in women with gynecologic malignancies. Gynecol Oncol. 2001 Sep;82(3):456-63.  PMID: 11520140
16. Mundt, AJ, Lujan, AE, Rotmensch, J, et al. Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1330-7.  PMID: 11955746
17. Brixey, CJ, Roeske, JC, Lujan, AE, Yamada, SD, Rotmensch, J, Mundt, AJ. Impact of intensity-modulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2002 Dec 1;54(5):1388-96.  PMID: 12459361
18. Mundt, AJ, Mell, LK, Roeske, JC. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys. 2003 Aug 1;56(5):1354-60.  PMID: 12873680
19. Roeske, JC, Bonta, D, Mell, LK, Lujan, AE, Mundt, AJ. A dosimetric analysis of acute gastrointestinal toxicity in women receiving intensity-modulated whole-pelvic radiation therapy. Radiother Oncol. 2003 Nov;69(2):201-7.  PMID: 14643959
20. Chen, MF, Tseng, CJ, Tseng, CC, Kuo, YC, Yu, CY, Chen, WC. Clinical outcome in posthysterectomy cervical cancer patients treated with concurrent Cisplatin and intensity-modulated pelvic radiotherapy: comparison with conventional radiotherapy. Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1438-44.  PMID: 17394944
21. Chen, MF, Tseng, CJ, Tseng, CC, Yu, CY, Wu, CT, Chen, WC. Adjuvant concurrent chemoradiotherapy with intensity-modulated pelvic radiotherapy after surgery for high-risk, early stage cervical cancer patients. Cancer J. 2008 May-Jun;14(3):200-6.  PMID: 18536561
22. Hsieh, CH, Wei, MC, Lee, HY, et al. Whole pelvic helical tomotherapy for locally advanced cervical cancer: technical implementation of IMRT with helical tomotherapy. Radiat Oncol. 2009;4:62.  PMID: 20003321
23. Hasselle, MD, Rose, BS, Kochanski, JD, et al. Clinical Outcomes of Intensity-Modulated Pelvic Radiation Therapy for Carcinoma of the Cervix. Int J Radiat Oncol Biol Phys. 2010 Aug 12.  PMID: 20708346
24. Frank, SJ, Rosenthal, DI, Petsuksiri, J, et al. Intensity-modulated radiotherapy for cervical node squamous cell carcinoma metastases from unknown head-and-neck primary site: M. D. Anderson Cancer Center outcomes and patterns of failure. Int J Radiat Oncol Biol Phys. 2010 Nov 15;78(4):1005-10.  PMID: 20207504
25. Rochet, N, Sterzing, F, Jensen, AD, et al. Intensity-modulated whole abdominal radiotherapy after surgery and carboplatin/taxane chemotherapy for advanced ovarian cancer: phase I study. Int J Radiat Oncol Biol Phys. 2010 Apr;76(5):1382-9.  PMID: 19628341
26. Macchia, G, Cilla, S, Ferrandina, G, et al. Postoperative intensity-modulated radiotherapy in low-risk endometrial cancers: final results of a Phase I study. Int J Radiat Oncol Biol Phys. 2010 Apr;76(5):1390-5.  PMID: 19800180
27. Kidd, EA, Siegel, BA, Dehdashti, F, et al. Clinical outcomes of definitive intensity-modulated radiation therapy with fluorodeoxyglucose-positron emission tomography simulation in patients with locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2010 Jul 15;77(4):1085-91.  PMID: 19880262
28. Milano, MT, Jani, AB, Farrey, KJ, Rash, C, Heimann, R, Chmura, SJ. Intensity-modulated radiation therapy (IMRT) in the treatment of anal cancer: toxicity and clinical outcome. Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):354-61.  PMID: 16168830
29. Salama, JK, Mell, LK, Schomas, DA, et al. Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: a multicenter experience. J Clin Oncol. 2007 Oct 10;25(29):4581-6.  PMID: 17925552
30. Devisetty, K, Mell, LK, Salama, JK, et al. A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy. Radiother Oncol. 2009 Nov;93(2):298-301.  PMID: 19717198
31. Pepek, JM, Willett, CG, Wu, QJ, Yoo, S, Clough, RW, Czito, BG. Intensity-Modulated Radiation Therapy for Anal Malignancies: A Preliminary Toxicity and Disease Outcomes Analysis. Int J Radiat Oncol Biol Phys. 2010 Mar 16.  PMID: 20231064
32. Hodges, JC, Das, P, Eng, C, et al. Intensity-modulated radiation therapy for the treatment of squamous cell anal cancer with para-aortic nodal involvement. Int J Radiat Oncol Biol Phys. 2009 Nov 1;75(3):791-4.  PMID: 19231109
33. Zampino, MG, Magni, E, Leonardi, MC, et al. Concurrent cisplatin, continuous infusion fluorouracil and radiotherapy followed by tailored consolidation treatment in non metastatic anal squamous cell carcinoma. BMC Cancer. 2011;11:55.  PMID: 21291546
34. Kachnic, LA, Tsai, HK, Coen, JJ, et al. Dose-painted Intensity-modulated Radiation Therapy for Anal Cancer: A Multi-institutional Report of Acute Toxicity and Response to Therapy. Int J Radiat Oncol Biol Phys. 2010 Nov 20.  PMID: 21095071
35. Pepek, JM, Willett, CG, Wu, QJ, Yoo, S, Clough, RW, Czito, BG. Intensity-modulated radiation therapy for anal malignancies: a preliminary toxicity and disease outcomes analysis. Int J Radiat Oncol Biol Phys. 2010 Dec 1;78(5):1413-9.  PMID: 20231064
36. Bazan, JG, Hara, W, Hsu, A, et al. Intensity-modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal. Cancer. 2011 Feb 1.  PMID: 21287530
37. NCCN Clinical Practice Guidelines in Oncology™. Gastric Cancer v 1.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
38. NCCN Clinical Practice Guidelines in Oncology™. Hepatobiliary Cancers v 1.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf
39. NCCN Clinical Practice Guidelines in Oncology™. Pancreatic Adenocarcinoma v 2.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
40. NCCN Clinical Practice Guidelines in Oncology™. Cervical Cancer v 1.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf
41. NCCN Clinical Practice Guidelines in Oncology™. Ovarian Cancer v 2.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
42. NCCN Clinical Practice Guidelines in Oncology™. Uterine Neoplasms v 1.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf
43. NCCN Clinical Practice Guidelines in Oncology™. Anal Carcinoma v 2.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/anal.pdf
44. NCCN Clinical Practice Guidelines in Oncology™. Colon Cancer v 3.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
45. NCCN Clinical Practice Guidelines in Oncology™. Rectal Cancer v 4.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
46. NCCN Clinical Practice Guidelines in Oncology™. Bladder Cancer v 2.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
47. NCCN Clinical Practice Guidelines in Oncology™. Kidney Cancer v 2.2011. [cited 04-08-2011]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf
48. Randall, ME, Ibbott, GS. Intensity-modulated radiation therapy for gynecologic cancers: pitfalls, hazards, and cautions to be considered. Semin Radiat Oncol. 2006 Jul;16(3):138-43.  PMID: 16814153

CROSS REFERENCES

Intensity Modulated Radiation Therapy (IMRT) of the Breast and Lung, Regence Medical Policy Manual, Medicine, Policy No. 136

Intensity Modulated Radiation Therapy (IMRT) of the Prostate, Regence Medical Policy Manual, Medicine, Policy No. 137

Intensity Modulated Radiation Therapy (IMRT) of the Head and Neck, Regence Medical Policy Manual, Medicine, Policy No. 138

Radioembolization for Primary and Metastatic Tumors of the Liver, Regence Medical Policy Manual, Medicine, Policy No. 140

Medicine Section Table of Contents