British Journal of Radiology (2006) 79, 497-503
© 2006 British Institute of Radiology
doi: 10.1259/bjr/43441736
Intensity-modulated radiation therapy in the treatment of gastric cancer: early clinical outcome and dosimetric comparison with conventional techniques
M T Milano, MD, PhD
1,2
M C Garofalo, MD
3
S J Chmura, MD, PhD
1
K Farrey, MS
1
C Rash, CMD
1
R Heimann, MD, PhD
4 and
A B Jani, MD
1
1 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, 2 Department of Radiation Oncology, University of Rochester, Rochester, NY 14642, 3 Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, 4 Division of Radiation Oncology, University of Vermont, Burlington, VT 05401, USA
Correspondence: Ashesh B Jani, University of Chicago, Department of Radiation and Cellular Oncology, MC 9006, Chicago, IL 60637, USA.
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Abstract
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The purpose of this study was to assess the efficacy and toxicity of intensity-modulated radiation therapy (IMRT) in the treatment of gastric cancer. Seven patients with gastric cancer were treated with IMRT. Six patients (all Stage III) received post-operative chemoradiotherapy with concurrent 5-fluorouracil and leucovorin. One received planned pre-operative radiation, though did not proceed to surgery. All patients were planned to receive 50.4 Gy in 1.8 Gy fractions. IMRT planning was compared with opposed anterior-posterior: posterior-anterior (AP/PA) and 3-field conventional three-dimensional plans. When compared with either AP/PA or 3-field plans, IMRT significantly reduced the volume exceeding the threshold dose of the liver and at least one kidney. Target coverage with IMRT was excellent, with 98±1% of the target receiving 
100% of the dose. Compared with AP/PA and 3-field plans, IMRT plans had a greater percentage of target receiving the prescribed dose, but also a greater volume receiving >110% of the dose. IMRT was well tolerated; no patients developed acute gastrointestinal toxicity greater than grade 2. All seven experienced grade 2 nausea, three had grade 2 diarrhoea and two had grade 2 oesophagitis. Weight loss ranged from 0–12% (mean 6.1% and median 5.8%). IMRT in the treatment of gastric malignancies reduces the mean and above threshold doses to critical normal tissues. In an initial cohort of seven patients, 50.4 Gy delivered by IMRT is well tolerated and safe.
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Introduction
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Gastric carcinoma is an uncommon malignancy in North America, yet it represents the eighth leading cause of cancer death in the USA. In 2004, approximately 21 860 new cases of gastric cancer were estimated to occur in the USA and approximately 11 550 deaths are expected as a result [1]. Due to the lack of a cost-effective screening tool, gastric cancer is often diagnosed at an advanced stage. Surgery is the cornerstone of the treatment for resectable advanced stage gastric cancer. Post-operatively, the locoregional failure rate is approximately 40% and approximately half of those failures represent the only site of failure [2, 3]. In the setting of locally advanced (T3–4 and/or node positive) non-metastatic disease, adjuvant chemoradiotherapy has been established as the standard of care in the USA based upon the recently reported results of the Gastric Surgical Adjuvant Trial Intergroup 0116 trial [4]. This trial demonstrated a statistically significant benefit in relapse-free survival (48% versus 31%, p<0.001) and overall survival (50% versus 41%, p = 0.01) with the use of adjuvant chemoradiotherapy when compared with surgery alone. Adjuvant therapy also reduced the percentage of failures attributable to local failure (29% vs 19%). Since this landmark trial was reported, the increased use of radiation therapy in the adjuvant treatment of gastric cancer prompted the publication of a consensus report reviewing the details related to radiotherapy delivery technique [5]. According to this consensus report, "parallel-opposed AP/PA fields are considered the most practical arrangement for the overwhelming majority of post-operative adjuvant radiotherapy cases".
The toxicity associated with adjuvant chemoradiation using traditional techniques is significant. Treatment volumes in the post-operative setting are necessarily large to account for the patterns of failure established in previous surgical studies [2, 3]. Typical target volumes include the stomach bed (to include surgical clips), a portion of the left hemi-diaphragm, and draining lymphatics at risk. The standard target dose of 45 Gy well exceeds the tolerance of several surrounding critical normal tissues (most notably the kidneys and liver). As a result, conventional treatment volumes are often tailored out of the fear of potential kidney and liver damage. By underdosing portions of the target, local control and survival may be compromised. Through inverse planning, intensity-modulated radiation therapy (IMRT) allows for more conformal dose delivery and selective sparing of critical structures such as the kidneys and liver, and may therefore allow for more complete target coverage to full-dose. Locoregional control may be improved through better target coverage and treatment toxicity may be reduced through the use of IMRT. We previously published our experience of using IMRT in the treatment of pancreatic and anal malignancies [6, 7]. Since 2001, our institution has routinely treated gastric cancer patients with post-operative chemotherapy combined with IMRT. Here we report the early clinical outcome of our single institution experience of seven patients treated for gastric cancer with IMRT, with emphasis on toxicity outcome, and the results of a dosimetric comparison with traditional radiotherapy delivery techniques.
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Materials and methods
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Between March 2001 and April 2004, seven consecutive non-metastatic patients with adenocarcinoma of the stomach were treated with IMRT. Six patients received post-operative chemoradiotherapy (CRT) with concurrent 5-fluorouracil and leucovorin, using chemotherapy doses and scheduling as described in the recently reported Intergroup trial [4]. Two of these six patients, treated in early 2001, were not offered additional chemotherapy following radiation based on physician preference. One 87-year-old patient with symptomatic bleeding received planned pre-operative radiation (without concurrent chemotherapy because of comorbidities), since upfront surgery would have been delayed until a pacemaker revision. However, she never proceeded to surgery because of the comorbidities. All patients were planned to receive 50.4 Gy in 1.8 Gy fractions, except for the patient treated pre-operatively, who was prescribed 45 Gy to an initial planned target volume (PTV) with a 5.4 Gy boost to the gross tumour. For the purpose of dosimetric comparisons (described below) this patient was planned similarly to the others (i.e. 50.4 Gy with no boost PTV). The higher dose of 50.4 Gy was chosen in an attempt to improve locoregional control, and because the IMRT dose–volume histograms (DVHs) suggested that it could be safely delivered.
All six patients who underwent resection had a D2 resection, including subtotal (n = 4) or total gastrectomy (n = 2), resection of perigastric and second echelon lymph nodes as described by the Japanese classification [8, 9].
Simulation and target contouring
Patients underwent CT based simulation in the supine position (PQ5000 CT Simulator; Marconi Medical Systems, Cleveland, OH) with 4 mm CT slices. A custom immobilization device (Alpha Cradle; Smithers Medical Product, Inc., North Canton, OH) was used to minimize set-up variability. The pre-operative CT scan was image correlated to the CT simulation scan using the AcQSim VoxelQ software package. The PTV and normal structures (kidneys, liver and spinal cord) were manually contoured onto the CT scan slices following the ICRU 50 recommendations [10]. The clinical target volume (CTV) was contoured on axial CT scan slices. The CTV typically included the original tumour volume, operative bed (as defined by the operative note, pathologic findings, surgical clips and discussion with the surgeon) and the draining lymphatics at risk. The gross tumour volume (GTV) was entered on the single patient treated prior to planned surgery. The radiation dose was prescribed to a PTV, which was generated by expanding the CTV by 1 cm. The PTV design incorporated set-up uncertainty and organ motion [11]. Normal structures were also entered, including the kidneys, liver and spinal cord.
IMRT planning
IMRT plans were generated using commercial inverse planning software (CORVUS, versions 3.0-5.0; NOMOS Corp., Sewickley, PA), which produces optimal intensity-modulated profiles using a simulated annealing algorithm. Dynamic multileaf collimators were used to shape the fields. Eight to nine-field coplanar plans were used. Typical angles were 40° increments starting from 0° to 320° (US convention). However, posterior fields that overdosed one kidney were usually removed (hence making an 8-field plan) or angled away from the kidney.
The PTV and normal structure dose–volume constraints were iteratively adjusted to ensure optimal target coverage while minimizing dose to the kidneys, liver and spinal cord, thus optimizing the PTV and normal tissue DVHs [12]. Typical input parameters were defined on an individual basis for each patient, and thus varied from patient to patient, depending on the geometry of the PTV relative to the normal structures. Table 1
exemplifies the input parameters for the normal structures in two different patients. Generally, the input parameters for the PTV were <2% of the PTV receiving <50.4 Gy with a maximum of 54.0 Gy.
The IMRT plans were optimized to minimize the volume of PTV receiving <95% of the prescribed dose and the volume receiving > 110% of the prescribed dose. Generally, the prescription dose was normalized to the 90–95% isodose line. The initial plans were considered acceptable with <2–4% of the PTV receiving <100% of the prescribed dose, <5% of the PTV receiving >110% and <1% receiving >115%.
Because the normal tissue DVHs generated by CORVUS ignores regions of overlap with the PTV, the CORVUS IMRT plans were exported into PlanUNC [13] for the purpose of dosimetric comparison with conventional radiation plans.
Comparison of three-dimensional AP/PA plans to IMRT plans
Three-field (3F) and opposed anterior-posterior: posterior-anterior (AP/PA) (2F) 3DRT plans were generated for comparison with IMRT plans for the last 6 of 7 patients treated with IMRT (for one patient, the CT scan with contoured structures was unable to be recovered from the electronic archives). The 3F plan included a left lateral and AP/PA fields. 3F and 2F plans were generated using PlanUNC [13]. Segmented fields, variable weighting of fields and wedges were used to optimize the plan so as to improve dose homogeneity. With the 3F plan, plans were chosen to minimize right kidney dose without compromising PTV coverage. At a minimum, 2F and 3F plans were acceptable only if >95% of the volume received >98% of the prescribed dose. Normalization was typically set at 99–100% of the prescription dose. Custom blocks were used (1 cm margin around the PTV in each beam's eye view). All fields were coplanar. 6 MV and 18 MV photons were used with the 3F and 2F plans, while 6 MV photons were used with the IMRT plans. DVHs were obtained for the PTV, kidneys, liver and spinal cord.
Acute toxicity was scored using RTOG morbidity scoring criteria [14]. Dosimetric endpoints for the target and critical structures were compared using the two tailed paired t-test.
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Results
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Seven patients with gastric cancer were treated with IMRT. The patient characteristics are outlined in Table 2. All six post-operatively treated patients had pathological stage IIIa-IIIb disease. Tumours were located in the antrum (n = 4) and lesser curvature (n = 3).
Dosimetric comparison between conventional and IMRT plans
To demonstrate the differences in dose distribution, Figure 1 shows isodose curves on an axial slice for one patient for IMRT, 2F and 3F plans. Additionally, Figure 2 shows the DVH curves for the organs at risk for one representative patient. Table 3 summarizes the mean doses to the PTV, kidneys and liver for 2F, 3F and IMRT plans. Compared with the 2F plan, IMRT significantly reduced the mean dose to the left kidney. Compared with the 3F plan, IMRT significantly reduced the mean dose to the liver and right kidney, while the reduction in the dose to the left kidney was not significant.
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Figure 1. Isodose curves on an axial slice for a representative patient for: (a) 2F (AP/PA) plan, (b) 3F plan, and (c) IMRT plan.
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Figure 2. Dose–volume histogram (DVH) curves for the organs at risk for a representative patient. (a) Liver, (b) spinal cord, (c) left kidney, and (d) right kidney. [y-axis: %Volume; x-axis: Dose (Gy); Colour Scheme- Blue: opposed anterior-posterior: posterior-anterior (AP/PA) plan; Red: 3F Plan; Green: IMRT plan].
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Table 4 summarizes the dosimetric endpoint analysis. Table 4a summarizes the volume of the PTV receiving greater than 50.4 Gy and 55.4 Gy. Table 4b summarizes the volume of critical structures receiving greater than the threshold dose [15]. Compared with 2F planning, IMRT significantly reduced the volume of left kidney receiving >20 Gy. Compared with 3F planning, IMRT significantly reduced the volume of right kidney receiving >20 Gy, and the volume of liver receiving >30 Gy.
The mean PTV dose as well as the volume receiving >55.4 Gy were greater for the IMRT plans, though compared with 3F, neither parameter was significantly different. The maximum doses for 2F, 3F and IMRT plans were 109%±3%, 108%±3% and 115±2%, respectively, with IMRT being significantly greater than 2F of 3F.
Clinical/toxicity outcome
In this small cohort of patients, 3 of 7 are long term survivors (>2 years after diagnosis) and remain without evidence of disease. One died more than a year after diagnosis, after developing a malignant pleural effusion at 9 months. Two died from metastatic disease and rapid deterioration at 7 months and 18 months following diagnosis (both patients did not receive chemotherapy immediately following radiation); it is not known if these two patients had a component of local and/or regional failure. The 87-year-old patient treated with planned pre-operative radiation had a stroke preceded by a fall and development of an interventricular haemorrhage (5 months after completing radiotherapy) and died 8 months after diagnosis.
All patients completed their planned course of treatment with no planned or unplanned treatment breaks and no reduction or discontinuation of chemotherapy. Chemoradiotherapy with IMRT was well tolerated with no grade 3 acute toxicity occurring during radiotherapy. Acute gastrointestinal and haematological toxicity is summarized in Table 5. Acute weight loss (up to 1 month post-radiation) ranged from no loss (1 patient) to a maximum of 12.3% weight loss, with a mean percentage of 6.1%±4.7% and median of 5.8%. Skin toxicity was grade 0–1 in all patients. Of the four patients who received chemotherapy after radiation, two (50%) had grade 3 haematological (WBC) toxicity, occurring after the last dose of chemotherapy in both patients. No abnormalities were detected on laboratory assessment of kidney function (as compared with pre-treatment/baseline values) for any of the seven patients, either during treatment or on last available clinic follow-up visit; one patient had elevated liver enzymes approximately 4 months after the completion of RT.
Although no late toxicity has been seen, the number of long term survivors is too small in this series to permit detailed analysis.
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Discussion
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IMRT in the treatment of gastric cancer has the potential of lowering treatment related toxicity. To date, little has been published on the use of IMRT with gastric cancer.
The University of Heidelberg has published two papers comparing the dose distribution of IMRT versus other planning modalities. In the first study, one patient was planned to 45 Gy with the following approaches: 8 field step and shoot IMRT (planned with CORVUS using multiple couch angles), conventional 4-field box (4F), 4F with an off-kidney boost after 16.2 Gy and a non-coplanar 4F plan with a 90° couch kick and gantry angle, to direct the beam off of the caudal kidneys [16]. IMRT reduced the median dose to the kidneys (particularly the left kidney) and liver; the doses that were exceeded by 30% and by 60% of the volumes (both liver and kidneys) were also reduced with IMRT. In a follow-up paper with 15 patients, IMRT was compared against AP/PA, 4F and serial tomotherapy [17]. IMRT reduced dose to the left kidney (at the expense of greater spinal cord dosing) as compared with 4F, with a slight reduction as compared with AP/PA. Compared with 4F, IMRT more consistently produced high quality plans, as evidenced by the reduced standard deviation of the mean doses and doses that were exceeded by 30% and by 60% of the volumes. The dosing of normal tissues was not significantly different between IMRT and serial tomotherapy, though serial tomotherapy was superior with respect to conformality and homogeneity.
Princess Margaret Hospital planned 20 gastric cancer patients to receive 45 Gy with conventional 5F coplanar plans versus 7–9 field IMRT plans, generated by the CADPLAN Helios planning system [18]. Three reviewers examined the plans, with IMRT being preferred in 89%, with subjectively better PTV coverage in 86%, kidney sparing in 69% liver sparing in 71%, and spinal cord sparing in 74%.
An Australian study compared AP/PA with a 3D conformal technique using a mono-isocentric split field technique [19]. The 3D conformal technique improved mean and threshold dose to the kidneys and spinal cord, but not the liver. Memorial Sloan Kettering recently investigated the use of IMRT in four patients with gastric lymphoma, whose PTV had a high degree of overlap with the kidneys. IMRT tended to improve kidney and liver sparing [20].
The present study confirms the efficacy of IMRT in reducing kidney and liver doses. IMRT, planned with dynamic multileaf collimation, was compared with both the standard 2F AP/PA approach as well as a 3-field technique. As in the Heidelberg study, we used CORVUS planning software. Two differences are that our IMRT planning used dynamic multileaf collimation, and that the IMRT dose matrices were exported into PLUNC, allowing inclusion of normal structure volumes that overlap with PTV. We also prescribed to a higher dose, 50.4 Gy versus 45.0 Gy.
Our data demonstrate that IMRT offers better sparing of the right kidney compared with conventional 3F planning, with significantly lower mean dose and volume above threshold dose [15]; and IMRT offers better sparing of the left kidney as compared with 2F planning, with lower mean dose and reduced volume above threshold dose (the latter of which was not significant). IMRT also affords liver sparing. As expected from the use of the additional field in the 3F arrangement, the liver dose increases dramatically with attempts to improve target coverage as compared with 2F planning. IMRT achieves similarly excellent target coverage as compared with 3F planning, while reducing the mean liver dose and volume above threshold dose [15]. In part, these improvements in relation to kidney and liver dose reduction with the use of IMRT may be due to reducing entrance and exit dose to these organs from beam angle selection.
To our knowledge, this study is the first to report clinical outcome in gastric cancer patients treated with IMRT. With respect to acute toxicity, patients fared remarkably well (albeit in a very small series), particularly since a higher than standard dose (50.4 Gy vs 45.0 Gy) was administered. There was no grade 3 or greater toxicity during radiation and all patients completed their planned course of chemoradiotherapy. In the Intergroup trial, 33% experienced grade 3 or greater gastrointestinal toxicity and 64% completed the treatment as planned. Grade 3 haematological toxicity was seen in the week following post-radiation chemotherapy in 2/4 patients, a percentage similar to that seen in the Intergroup trial (54% grade 3 haematological toxicity).
In summary, IMRT offers improved sparing of normal structures, allowing a dose of 50.4 Gy to be delivered to the PTV. In this small series of patients, treatment was well tolerated with acceptable toxicity, seemingly improved as compared with the Intergroup trial. IMRT in the treatment of gastric cancer warrants further study.
Received for publication June 7, 2005.
Revision received August 23, 2005.
Accepted for publication October 7, 2005.
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Abstract
Introduction
