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Comparison of intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy as adjuvant therapy for gastric cancer†
Article first published online: 13 MAY 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 16, pages 3943–3952, 15 August 2010
How to Cite
Minn, A. Y., Hsu, A., La, T., Kunz, P., Fisher, G. A., Ford, J. M., Norton, J. A., Visser, B., Goodman, K. A., Koong, A. C. and Chang, D. T. (2010), Comparison of intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy as adjuvant therapy for gastric cancer. Cancer, 116: 3943–3952. doi: 10.1002/cncr.25246
Presented at the American Society for Radiation Oncology Annual Meeting, Chicago, Illinois, November 1-5, 2009.
- Issue published online: 4 AUG 2010
- Article first published online: 13 MAY 2010
- Manuscript Accepted: 15 DEC 2009
- Manuscript Revised: 12 NOV 2009
- Manuscript Received: 24 JUN 2009
- intensity-modulated radiotherapy (IMRT);
- adjuvant therapy;
- radiation outcomes
The current study was performed to compare the clinical outcomes and toxicity in patients treated with postoperative chemoradiotherapy for gastric cancer using intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3D CRT).
Fifty-seven patients with gastric or gastroesophageal junction cancer were treated postoperatively: 26 with 3D CRT and 31 with IMRT. Concurrent chemotherapy was capecitabine (n = 31), 5-fluorouracil (5-FU) (n = 25), or none (n = 1). The median radiation dose was 45 Gy. Dose volume histogram parameters for kidney and liver were compared between treatment groups.
The 2-year overall survival rates for 3D CRT versus IMRT were 51% and 65%, respectively (P = .5). Four locoregional failures occurred each in the 3D CRT (15%) and the IMRT (13%) patients. Grade ≥2 acute gastrointestinal toxicity was found to be similar between the 3D CRT and IMRT patients (61.5% vs 61.2%, respectively) but more treatment breaks were needed (3 vs 0, respectively). The median serum creatinine from before radiotherapy to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but increased in the 3D CRT group from 0.80 mg/dL to 1.0 mg/dL (P = .02). The median kidney mean dose was higher in the IMRT versus the 3D CRT group (13.9 Gy vs 11.1 Gy; P = .05). The median kidney V20 was lower for the IMRT versus the 3D CRT group (17.5% vs 22%; P = .17). The median liver mean dose for IMRT and 3D CRT was 13.6 Gy and 18.6 Gy, respectively (P = .19). The median liver V30 was 16.1% and 28%, respectively (P < .001).
Adjuvant chemoradiotherapy was well tolerated. IMRT was found to provide sparing to the liver and possibly renal function. Cancer 2010. © 2010 American Cancer Society.
There were expected to be 21,130 new cases of gastric cancer reported in the United States in 2009.1 Locoregional recurrence is a significant problem with a reported rate of 23% to 38%,2-4 emphasizing the need for adjuvant local therapy. In the Intergroup 0116 trial, adjuvant chemoradiotherapy improved 3-year median survival to 36 months compared with 27 months in the surgery only arm,5 establishing chemoradiotherapy as the standard adjuvant therapy for patients with high-risk, resected gastric adenocarcinoma.
Large radiation fields are required to adequately cover the resection bed and lymph node regions at risk of harboring micrometastatic disease. However, given the large treatment volumes together with concurrent chemotherapy, toxicities may be considerable. Patients who received chemoradiotherapy in the Intergroup study had a 41% rate of grade 3 toxicity, a 32% rate of grade 4 toxicity, and a 1% rate of grade 5 toxicity. In addition, 17% of patients had to withdraw from therapy early.5
The standard target dose of 45 grays (Gy) exceeds the tolerance of some critical normal tissues, limiting the ability to deliver higher doses. Intensity-modulated radiotherapy (IMRT) has been shown in multiple studies to have the potential of reducing dose to normal critical structures,6-8 but clinical outcomes are limited.
Given the poor overall prognosis and significant toxicity due to chemotherapy and large radiation fields, there is a need to improve standard treatment. IMRT may allow for higher doses to improve control as well as decrease acute toxicity by limiting dose to normal structures. Since 2002, IMRT has been used routinely for the treatment of gastric cancer as part of chemoradiotherapy after surgical resection. The objective of the current study was to evaluate clinical outcomes and toxicity in patients treated with postoperative chemoradiotherapy for gastric cancer with IMRT compared with a group of patients treated with 3-dimensional conformal radiotherapy (3D CRT) at a single institution.
MATERIALS AND METHODS
From December 1998 to June 2008, 61 patients with nonmetastatic gastric or gastroesophageal (GE) junction cancer were treated with postoperative radiotherapy at Stanford University. Two patients treated with IMRT and 2 patients treated with 3D CRT who did not complete their radiation course were excluded, leaving 57 patients for this analysis. Twenty-six patients (46%) received 3D CRT and 31 patients (54%) received IMRT. Earlier patients were treated with 3D CRT; however, there was a gradual shift of practice toward IMRT beginning in 2002. All patients had pathology confirmed at Stanford. Disease was limited to the stomach or GE junction and regional lymph nodes. Patients were staged according to the American Joint Committee on Cancer tumor-node-metastasis staging (TNM) classification.9
All patients underwent routine systemic workup and disease evaluation that included history and physical examination, routine laboratory studies, computed tomography (CT) of the chest and abdomen, and esophagogastroduodenoscopy with biopsy. Fifty-three patients (93%) received chemotherapy that was fluorouracil-based (5-fluorouracil [5-FU] or capecitabine) with or without carboplatin before the start of radiotherapy, the latter regimen being part of an institutional protocol. One patient received epirubicin, oxaliplatin, and capecitabine (EOX). The majority of patients received 2 cycles before radiation. Patients received concurrent chemotherapy with capecitabine (n = 31), 5-FU (n = 25), or none (n = 1). After the completion of radiotherapy, 45 patients (79%) received 1 to 2 cycles of the same chemotherapy that was given before radiation, as directed by their medical oncologist.
Specific characteristics of radiation treatment, including dose and fractionation, were determined by reviewing radiation treatment charts and computerized radiation plans. All patients underwent CT-based treatment planning and were immobilized using an Alpha Cradle (Smithers Medical Products Inc, Hudson, OH). The target and normal adjacent structures were contoured on the planning CT scan. The clinical target volume (CTV) in general followed previously published guidelines10, 11 and included the preoperative stomach volume, surgical bed including the gastric remnant, and perigastric lymph nodes. Other lymph node areas such as mediastinal, porta hepatis, splenic hilum, pancreaticoduodenal, and peripancreatic were included if at risk based on primary tumor location or involvement of lymph nodes pathologically. For the bowel, the intestinal loops outside the planning treatment volume (PTV) were contoured, not the whole abdominal space. To account for daily setup error and organ motion, the CTV to PTV expansion was typically 5 to 10 mm. Normal structures were also contoured, including kidneys, liver, spinal cord, and bowel.
Radiation plans for 3D CRT were generated using FOCUS (Focus, CMS, Elekta, Maryland Heights, MO) for 23 patients or Eclipse (Eclipse, Varian, Palo Alto, CA) for 3 patients. Patients were treated with either a 3- or 4-field technique to 43.2 to 50.4 Gy (median, 45 Gy), 5 days a week. IMRT plans were generated using commercial planning software (Eclipse). The PTV received a median dose of 45 Gy (range, 41.4-54 Gy) with a median fraction size of 1.8 Gy (range, 1.8-2.08 Gy). Although the median doses were similar between the treatment groups, more patients received >45 Gy in the IMRT group than in the 3D CRT group (10 vs 2, respectively). For the 12 patients who received >45 Gy, the additional 5 to 9 Gy were given a sequential conedown or simultaneous integrated boost. Six patients with positive margins and 2 patients with close margins received >45 Gy. Twenty-three patients treated with IMRT were treated with respiratory gating while all other patients were treated with free breathing. Beam energies used included 6 megavolts (MV), 10 MV, 15 MV, or a mix of 6 and 15 MV.
Dose constraint guidelines used for IMRT planning included: 75% of the liver, <15 Gy; mean liver dose, <20 Gy; 70% of each kidney, <15 Gy or two-thirds of 1 kidney <18 Gy; and 95% of the bowel, <45 Gy. Maximum dose to the bowel was <54 Gy. For the purposes of planning, the bowel space was contoured. The spinal cord dose was limited to 45 Gy. The IMRT plans were normalized to 95% volume to get 100% of the dose. Guidelines were adhered to as closely as possible. For each patient, the plan was reviewed to ensure optimal target coverage while minimizing dose to the normal structures.
The dose volume histogram (DVH) parameters were compared between the 3D CRT group and the IMRT group. However, because of differences in patient anatomy, direct comparison is somewhat confounded. An additional analysis was performed comparing the volume that received ≥42.75 Gy (95% of 45 Gy) between the 2 patient groups to determine if more normal tissue was receiving near-prescription dose.
All patients were followed routinely with physical examinations, CT imaging, and serum measurements at 3- to 6-month intervals. The Kaplan-Meier method was used to calculate actuarial rates of locoregional control (LRC), disease-free survival (DFS), and overall survival (OS).12 Time to event was calculated as the time interval from the first date of radiation to the date of death or the first disease recurrence. Log-rank statistic was used to correlate various clinical and treatment characteristics with LRC, DFS, and OS. Multivariate analysis was not performed due to small patient numbers. All patients were seen at least weekly during radiation treatment, and acute toxicities were monitored. Toxicities were scored using the Common Terminology Criteria for Adverse Events, version 3.0. Gastrointestinal (GI) acute toxicity data were not available for 3 patients who received IMRT. Hematologic acute toxicity was not available for 1 patient who received IMRT. Differences in preradiation and most recent disease-free creatinine were tested using the Student t test for paired data. Median values of mean dose, percentage of kidney receiving ≥20 Gy (V20), and percentage of liver receiving ≥30 Gy (V30) for patients treated with 3D CRT were compared with IMRT using the Wilcoxon signed rank test.
Patient and Tumor Characteristics
Characteristics of the 57 patients are summarized in Table 1. The median age at diagnosis was 58.7 years (range, 28.9-82.8 years). The median follow-up for the 3D CRT patients was 1.3 years (range, 0.1-9.4 years), and the median follow-up for the IMRT patients was 1.3 years (range, 0.4-4.1 years). There was no difference between the 3D CRT and IMRT groups noted with respect to age at diagnosis, gender, grade of tumor, stage, percentage positive lymph nodes, margin status, and chemotherapy.
|3D CRT (n=26)||IMRT (n=31)||P|
|Age at diagnosis, y||Median (range)||58.6 (28.9-82.8)||58.7 (38.0-76.4)||.74|
|Gender||Man||16 (61.5%)||22 (71%)||.57|
|Woman||10 (38.5%)||9 (29.0%)|
|Grade||Well differentiated||0 (0%)||3 (9.7%)||.50|
|Moderately differentiated||6 (23.1%)||2 (6.5%)|
|Poorly differentiated||17 (65.4%)||25 (80.6%)|
|Grade not assessed||3 (11.5%)||1 (3.2%)|
|T classification||1||2 (7.7%)||1 (3.2%)||.43|
|2a/b||13 (50%)||13 (42%)|
|3||9 (34.6%)||16 (51.6%)|
|4||2 (7.7%)||1 (3.2%)|
|N classification||0||5 (19.2%)||3 (9.7%)||.55|
|1||11 (42.3%)||16 (51.6%)|
|2||5 (19.2%)||9 (29.0%)|
|3||5 (19.2%)||3 (9.7%)|
|Surgery||Ivor-Lewis esophagogastrectomy||6 (23.1%)||8 (25.8%)|
|Total gastrectomy||8 (30.8%)||10 (32.3%)|
|Subtotal gastrectomy||12 (46.2%)||13 (41.9%)|
|Location||GE junction||5 (19.2%)||9 (29.0%)|
|Cardia/proximal one-third||1 (3.8%)||3 (9.7%)|
|Body/middle one-third||5 (19.2%)||3 (9.7%)|
|Antrum/distal one-third||14 (53.8%)||13 (41.9%)|
|Diffuse||1 (3.8%)||3 (9.7%)|
|Surgical margins||Negative||20 (76.9%)||18 (58.1%)||.17|
|Close (<3 mm)||0 (0%)||7 (22.6%)|
|Positive||6 (23.1%)||6 (19.3%)|
|No. of lymph nodes dissected||Median (range)||20 (4-56)||19 (1-49)|
|No. of lymph nodes positive||Total (range)||5 (0-27)||5 (0-20)||1.0|
|% Positive (range)||32.3% (0-100%)||28.6% (0-88.2%)||.79|
|Total dose, Gy||Median (range)||45 (43.2-50.4)||45 (41.4-54)||.01a|
|Concurrent chemotherapy||5-FU||20 (77%)||5 (16%)|
|Capecitabine||5 (19%)||26 (84%)|
|None||1 (4%)||0 (0%)|
|Pre-RT and/or post-RT chemotherapy||5-FU||2 (7.7%)||2 (6.45%)||.74|
|Carboplatin/5-FU||17 (65.4%)||6 (19.4%)|
|Carboplatin/capecitabine||5 (19.2%)||19 (61.3%)|
|Capecitabine||0 (0%)||2 (6.45%)|
|EOX||0 (0%)||1 (3.2%)|
|None||2 (7.7%)||1 (3.2%)|
At the time of last follow-up, 20 patients had died of progressive disease, 4 were alive with progressive disease, and 33 patients were alive with no evidence of disease. The median OS (Fig. 1A) and DFS from the initiation of radiotherapy was 5.4 years and 4.7 years, respectively. The 2-year OS for the 3D CRT and IMRT groups was 51% and 65%, respectively (P = .5) (Fig. 1B). The 2-year DFS for the 3D CRT and IMRT groups was 60% and 54%, respectively (P = .8) (Fig. 1C). The 2-year local control rate for the 3D CRT and IMRT groups was 83% and 81%, respectively (P = .9) (Fig. 1D).
Four local-regional failures occurred each in the 3D CRT (15%) and the IMRT (13%) groups. Time to locoregional recurrence ranged from 3.9 to 56.0 months. In the 3D CRT group, 1 failure occurred at the anastomotic site and this patient simultaneously presented with liver metastases. This patient had a positive margin at the esophagus. In the IMRT group, 2 of the failures occurred at the anastomosis site. One patient had close surgical margins (2 mm) and also presented with pulmonary nodules. The second patient had negative surgical margins. A total of 17 patients developed distant metastases. The median time to distant metastasis was 8.7 months (range, 3.9-21.6 months).
On univariate analysis, T classification (T1-2 vs T3-4) was found to be significantly correlated with LRC, DFS, and OS (P = .03, P = .005, and P = .001, respectively). Patients with negative margins (P < .001 and P = .006) and <30% positive lymph nodes involved (P = .03 and P = .03) had improved DFS and OS, respectively. Patient gender, age, grade of tumor, N classification, and total radiation dose were not found to be significantly correlated with LRC, DFS, or OS in this series.
Acute and Long-Term Toxicity
Fourteen patients (24.6%) had feeding tubes placed before the initiation of radiotherapy. No feeding tube was placed during radiotherapy. Three patients required a treatment break of a median duration of 7 days due to toxicity in the 3D CRT group (range, 4-10 days), whereas no patient in the IMRT group required a treatment break. Grade 2 or higher acute GI toxicity was noted in 61.5% and 61.2% of patients in the 3D CRT and IMRT groups, respectively. Acute GI toxicity is shown in Table 2. Grade 2 or higher hematologic toxicity during radiotherapy was seen in 35% and 29% of the patients in the 3D CRT and IMRT groups, respectively. Only 8 (14.0%) patients experienced grade 3 nausea. Mean weight loss was 5.4 pounds (range, 0-18 pounds). Mean percent weight loss was 3.7% (range, 0 = .10.8%). Only 1 patient experienced grade 2 toxicity (10.8% weight loss) with respect to weight loss.
|Grade||Total Grade ≥2|
|Nausea||3D CRT||10 (39%)||4 (15%)||0 (0%)||14 (54%)|
|IMRTb||11 (36%)||4 (13)||0 (0%)||15 (49%)|
|Vomiting||3D CRT||4 (15%)||0 (0%)||0 (0%)||4 (15%)|
|IMRTb||1 (3%)||0 (0%)||0 (0%)||1 (3%)|
|Anorexia||3D CRT||8 (31%)||3 (12%)||0 (0%)||11 (43%)|
|IMRTb||8 (26%)||5 (16%)||0 (0%)||13 (42%)|
|Diarrhea||3D CRT||0 (0%)||0 (0%)||0 (0%)||0 (0%)|
|IMRTb||2 (7%)||0 (0%)||0 (0%)||2 (7%)|
Forty-nine patients had >6 months follow-up after the completion of radiotherapy. Late toxicity was noted for patients in the absence of progressive disease. Among the 3D CRT patients, 1 patient died of small bowel perforation requiring surgical intervention (grade 5). Grade 3 late toxicity was experienced by 3 patients who developed small bowel obstruction. Two patients developed grade 2 late toxicity (jaundice and esophagitis).
For the IMRT group, grade 3 late toxicity was experienced by 1 patient who had a stricture requiring surgery. Grade 2 late toxicity was experienced by 3 patients: 1 with gastritis, 1 with esophagitis, and 1 with an ulcer.
Among the patients treated with IMRT, the median preradiation serum creatinine and most recent disease-free postradiation level were both 0.80 mg/dL, respectively. The median length of time from preradiation creatinine to recent creatinine was 1.2 years (range, 0.3-4.0 years). An increase in the median creatinine levels in preradiation versus postradiation was observed among patients treated with 3D CRT (0.80 mg/dL and 1.0 mg/dL, respectively; P = .02). The median length of time between the preradiation creatinine and most recent disease-free creatinine was 0.9 years (range, 0.3-9.5 years).
DVH data are detailed in Table 3. The median volume receiving 42.75 Gy for 3D CRT versus IMRT was 1606 cm3 versus 1282.6 cm3, respectively (P = .048). Figure 2 shows an example of a plan for 3D CRT and IMRT. The median kidney mean dose of both kidneys as a single organ was higher in the IMRT group versus the 3D CRT group (13.9 Gy vs 11.1 Gy, P = .05). The median V20 for both kidneys as a single organ was lower for the IMRT group versus the 3D CRT group (18% vs 22%), but this difference was not found to be statistically significant (P = .18). The median right kidney mean dose was higher for the IMRT group versus the 3D CRT group (11.9 Gy vs 10.4 Gy; P = .04). There was no difference in V20 for the right kidney for the 3D CRT versus the IMRT group (P = .55). Similarly, the median left kidney mean dose was higher for the IMRT group (15.3 Gy) compared with the 3D CRT group (12.1 Gy), and this difference was nearly significant (P = .06). The median V20 for the left kidney was nonsignificantly lower in the IMRT group compared with the 3D CRT group (22.2% vs 32.0%; P = .31).
|Both kidneys, cGy||1158||1109||551-1927||1399.2||1388||537-2546||.05|
|Right kidney, cGy||951||1036||225-1689||1172||1197||291-2074||.04|
|Left kidney, cGy||1291||1205||269-2470||1624.6||1528.5||366-3401||.06|
The median mean liver dose for 3D CRT and IMRT was 18.6 Gy and 17.3 Gy, respectively (P = .19). The median liver volume treated above 30 Gy (V30) was 28% and 16.1%, respectively (P < .001), which was highly statistically significant. For the IMRT patients, the median bowel space maximum dose was 50.7 Gy (range, 48.1-61.5 Gy), V50 was 0.4 cc (range, 0-187.7 cc), and V45 was 297.5 cc (range, 133.3-871.8 cc). Bowel DVH data are not available for the 3D RT group.
Adjuvant combined chemoradiotherapy has become standard of care in the United States due to the landmark Intergroup 0116 trial.5 In this trial, patients were treated to 45 Gy using radiation fields that covered a large portion of the upper and mid-abdomen to encompass the preoperative tumor bed and regional lymph nodes, leading to significant side effects. As a result, 17% did not complete their therapy due to toxicity. In addition, 33% of the patients experienced grade 3 or higher GI toxicity. Given the formidable size of standard 2D or 3D fields, the desire to avoid the risk of acute toxicity likely contributed in part to the 35% deviations of the radiation plans that required corrections in that trial.
The outcomes for gastric cancer continue to be poor, and the toxicity from treatment with chemotherapy and 3D CRT is high. There is a need to improve the treatment for gastric cancer due to treatment-related morbidity. IMRT may allow us to increase dose in hopes of improving disease control while decreasing the toxicity profile previously observed with 3D CRT, and the toxicity noted in the current series compares favorably with the Intergroup 0116 trial. No treatment breaks were needed among patients treated with IMRT compared with those treated with 3D CRT. Compared with the 41% rate of grade 3 toxicity, the 32% rate of grade 4 toxicity, and the 1% rate of grade 5 toxicity noted in the Intergroup study, the IMRT patients in the current study had a 26% rate of grade 3 and no grade 4 or 5 GI toxicity. There was 10% grade 3 hematologic toxicity with no grade 4 or 5 toxicity, and these were typically observed at the initiation of RT, suggesting that these may be related to pre-RT chemotherapy treatment. Although differences in the chemotherapy regimens may confound this type of direct comparison, the toxicity profile with IMRT does appear to be tolerable. It should be noted, however, that the group of patients in the current study who were treated with 3D CRT also experienced a similarly low rate of grade ≥3 toxicity.
Recently, postoperative gastric cancer patients have been treated with IMRT at our institution in hopes of decreasing acute and late toxicity. This study was undertaken to compare the results of 3D CRT with those of IMRT. It is difficult to control for confounding variables when comparing patients from different time periods, and there are well-recognized limitations of retrospective studies of this kind. However, we believe that the 2 patient groups are well-balanced with respect to baseline, disease, and treatment characteristics, which is a relative strength of this study. Because of institutional standards, patients who received chemotherapy at Stanford during this study period were treated with a similar regimen, whereas those receiving chemotherapy at another institution had more varied drugs. The lack of significant differences in chemotherapy regimens (namely carboplatin-based versus noncarboplatin-based) is important because it can confound both the survival as well as toxicity analysis.
The most important finding in the current study is that disease outcome is not significantly different between patients treated with IMRT versus those treated with 3D CRT. We would not necessarily expect improvement in survival with IMRT without changes in dose or prevention of treatment-related morbidity and mortality. However, it is important to note that the implementation of IMRT has not caused a decrease in LRC or OS due to errors in defining target volumes or quality assurance. Therefore, to justify using IMRT, a reduction in acute and/or late toxicity should be demonstrated. In this study, no treatment breaks were required in the group receiving IMRT compared with 11.5% of patients in the 3D CRT group requiring a treatment break of a median of 7 days. No patients required the placement of a feeding tube during their radiotherapy. These results are particularly encouraging given that more patients in the IMRT group received higher doses of radiation.
Toxicity was not found to be worse in the IMRT group compared with the 3D CRT group despite the use of higher doses in more cases. In addition, the use of IMRT allowed for more conformal coverage of our PTV and less tissue needing to received ≥95% of the prescription dose despite higher prescription doses, as compared with the 3D CRT plans (P = .048).
We observed that IMRT, compared with 3D CRT planning, had improved sparing of the liver (V30 was 16.1% vs 28% for IMRT and 3D CRT, respectively; P < .001). Similarly, the median V20 for kidneys was lower in IMRT compared with 3D CRT, but this difference was not statistically different. Conversely, the mean dose was higher for the IMRT plans compared with the 3D CRT plans. The higher mean dose among the IMRT patients may be due to more patients receiving >45 Gy to the target. However, an important point to note is that these data are not based on replanning patients using the same CT data set for side-by-side comparison of DVH parameters. Rather, we analyzed the normal organ DVHs of radiation plans actually delivered to the patient to correlate short- and long-term toxicity. Thus, there may be variation in target definition, radiotherapy field design, and dose due to differences in patient anatomy, different treatment periods, and the individual preferences of multiple treating physicians.
Other institutions have also reported improvements in dose to normal structures. In a study comparing IMRT and 3D CRT plans at Princess Margaret Hospital, IMRT was preferred in 17 of 19 cases, chosen by blinded radiation oncologists.6 In 4 of the plans, the radiation oncologists were concerned because the spinal cord dose approached tolerance, and there were potential hotspots in the small bowel. However, the authors found that IMRT provided better PTV coverage and better sparing of the spinal cord, liver, kidneys, and heart in the majority of cases. It was believed that the cases in which the conformal plans were chosen could have been successfully treated with IMRT with an opportunity for further optimization. In addition, correction for organ motion was not done. The median kidney dose was reduced up to 50% in IMRT plans, in another study.7 In another small study, IMRT reduced the volume of left or right kidney receiving >20 Gy and the volume of liver receiving >30 Gy.8 No grade 3 acute toxicity during radiotherapy was noted in these patients treated to 50.4 Gy. Lastly, IMRT with oxaliplatin/capecitabine (XELOX) was shown to improve OS and disease DFS without late grade 2 renal toxicity.13
Similar to our study, other institutions have similarly reported mixed results when comparing IMRT with 3D CRT. In a study by Chung et al, a dosimetric advantage of IMRT over 3D CRT was not observed.14 They found that, although IMRT plans led to lower liver doses and improved PTV coverage, there was no significant reduction in kidney dose. Further optimizations were able to improve kidney, liver, and spinal cord doses. Another recent study showed only marginal benefit in the adjuvant therapy for gastric cancer with IMRT with respect to spine and kidney dose.15
In the current study, despite no clear advantage to kidney sparing with IMRT, there may still be some kidney function preservation. In the patients treated with 3D CRT, the serum creatinine increased from the pretreatment baseline level, whereas no such increase was observed in the IMRT patients. However, creatinine clearance may be a better measure for evaluating renal function. Jansen et al also showed that, with adjuvant 3D CRT, serum creatinine was elevated 1 year after treatment.16 To the best of our knowledge, this is the first study suggesting that IMRT can potentially preserve kidney function over 3D CRT. These results appear to suggest that the mean kidney dose, which was higher with IMRT, may not be as important for kidney preservation as much as the V20, which was lower with IMRT, because the threshold tolerance of the kidney is believed to be approximately 20 Gy. In the study by Jansen et al, both the V20 and mean kidney dose correlated with late renal function.14 Longer follow-up is needed to further evaluate kidney function and its relation to kidney dose.
Two studies have suggested that smaller fraction doses may decrease renal toxicity and may potentially improve renal tolerance. There was significant renal damage noted in guinea pig kidneys that received 80 to 81 Gy in 2- to 3-Gy fractions as compared with kidneys receiving the same total dose in a hyperfractionated regimen in 1-Gy fractions.17 Similarly, reducing the dose per fraction demonstrated decreased renal damage in mice that underwent total body irradiation in preparation for bone marrow transplantation.18 These data provide further support for the use of IMRT because it allows smaller fraction sizes to the kidney.
A limitation of the current study is the small patient numbers and short follow-up. Another limitation is that we do not have direct comparison of 3D CRT and IMRT for each patient, as some of the previous studies have done. However, the plans were optimized for each patient whether 3D CRT or IMRT was used and therefore we are comparing plans that were deemed acceptable for treatment at our institution. Finally, because 3D CRT patients were treated earlier in this series, there is unequal long-term follow-up lengths for the 2 treatment groups, although the median follow-up lengths and time between creatinine levels were similar. Further follow-up is certainly needed to reveal possible differences in late toxicity between the groups.
Although the data are not consistent in demonstrating an advantage of IMRT over 3D CRT, there may be some gains in acute toxicities with the use of IMRT because of generally decreased dose to normal organs such as bowel, kidney, and liver. In addition, IMRT may allow for dose escalation in the hopes to improve disease control, especially in cases such as close/positive margins, extranodal disease spread, or other situations believed to have a high risk of residual microscopic disease, without increasing the dose to critical structures. The incorporation of image guidance likely confers additional improvements. Further investigation is required to determine the true clinical benefit of IMRT for this disease, and we believe it is highly warranted given the generally poor outcomes of this disease and the high rate of treatment morbidity.
Although LRC is good with adjuvant chemoradiotherapy overall outcomes for gastric cancer remain poor. Improvements in both local and systemic therapy are required. Adjuvant chemoradiotherapy was well tolerated with either 3D CRT or IMRT, with similar acute and late toxicities reported. Despite higher doses used, IMRT provides sparing to the liver and possibly the kidneys. Although the dosimetric advantage of IMRT for the kidneys was not consistent, renal function appears to be preserved better. These results need to be validated with longer follow-up as well as in larger studies.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
- 9AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; 2002., , , et al.
- 14Can all centers plan intensity-modulated radiotherapy (IMRT) effectively? An external audit of dosimetric comparisons between three-dimensional conformal radiotherapy and IMRT for adjuvant chemoradiation for gastric cancer. Int J Radiat Oncol Biol Phys. 2008; 71: 1167-1174., , , et al.