|Year : 2015 | Volume
| Issue : 3 | Page : 623-629
Intensity modulated radiation therapy (IMRT) is not superior to three-dimensional conformal radiation (3DCRT) for adjuvant gastric radiation: A matched pair analysis
Supriya Chopra1, Aditi Agarwal2, Reena Engineer2, Tapas Dora1, Biji Thomas1, Supriya Sonawone1, Siji N Paul1, Sadhna Kannan3, Prachi Patil4, Shaesta Mehta4, Shyam Kishore Shrivastava2
1 Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer, Kharghar, Navi Mumbai, India
2 Departments of Radiation Oncology and Medical Physics, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India
3 Epidemiology and Clinical Trials Unit, Advanced Centre for Treatment Research and Education in Cancer, Kharghar, Navi Mumbai, India
4 Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India
|Date of Web Publication||9-Oct-2015|
Department of Radiation Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai - 410 210, Maharashtra
Source of Support: None, Conflict of Interest: None
Aims: To compare three-dimensional conformal radiation (3DCRT) and Intensity Modulated Radiation Therapy (IG-IMRT) for adjuvant gastric irradiation.
Subjects and Methods: From Jan 2010-Aug 2013, all patients undergoing 3DCRT and IG-IMRT were included. Systemic chemotherapy included 1 cycle before and 2 cycles after chemoradiation. Planning Target Volume (PTV) received 45 Gy/25 fractions/5 weeks with concurrent capcetabine 825 mg/m2 bid. Matched pair analysis was performed to evaluate imbalance in two cohorts if any. Common Toxicity Criteria for Adverse Event (CTCAE) vs 3.0 was used to record gastrointestinal (GI), hematological (HL), and renal toxicity during treatment and follow-up. Patterns of recurrence were documented. Mann-Whitney U test was used for statistical comparison.
Results: Of the 51 patients, 26 received 3DCRT and 25 IMRT. IMRT led to decrease in dose received by right and left kidney (12.4 Gy and 7.1 Gy and 29 Gy vs 8.2 Gy; P < 0.001). Overall, 17.6% and 19.6% patients had grade II GI and HL toxicity and 3.9% and 5.9% had grade III GI and HL toxicity. No difference was observed in acute grade II-V GI or HL toxicity (11.5% vs 24%, P = 0.07; 7.6% vs 20% P = 0.20) or late GI, HL, or renal toxicity between 3DCRT and IMRT. No difference was observed in patterns of local relapse (11.5% vs 12%, P = 0.14) or overall survival (39% and 38% (P = 0.97)) between 3DCRT and IMRT.
Conclusions: 3DCRT and IMRT are equivalent in terms of toxicity and local control.
Keywords: Gastric, Intensity modulated radiation therapy, three-dimensional conformal radiation, toxicity
|How to cite this article:|
Chopra S, Agarwal A, Engineer R, Dora T, Thomas B, Sonawone S, Paul SN, Kannan S, Patil P, Mehta S, Shrivastava SK. Intensity modulated radiation therapy (IMRT) is not superior to three-dimensional conformal radiation (3DCRT) for adjuvant gastric radiation: A matched pair analysis. J Can Res Ther 2015;11:623-9
|How to cite this URL:|
Chopra S, Agarwal A, Engineer R, Dora T, Thomas B, Sonawone S, Paul SN, Kannan S, Patil P, Mehta S, Shrivastava SK. Intensity modulated radiation therapy (IMRT) is not superior to three-dimensional conformal radiation (3DCRT) for adjuvant gastric radiation: A matched pair analysis. J Can Res Ther [serial online] 2015 [cited 2019 Nov 11];11:623-9. Available from: http://www.cancerjournal.net/text.asp?2015/11/3/623/150438
| > Introduction|| |
The results of South West Oncology Group (SWOG) 9008/ Intergroup study 0116 (INT0116) established adjuvant chemo-radiation and systemic chemotherapy as the standard of care in patients undergoing upfront surgical resection for gastric cancer.  The 10-year follow-up results of SWOG 9008/INT0116 continue to demonstrate sustained benefit in terms of overall survival (OS) as well as relapse free survival (RFS).  Though this benefit has been questioned in the setting of D2 dissection, a recent meta-analysis failed to identify patients who do not benefit from adjuvant chemo-radiation after D2 dissection.  In another meta-analysis of patients undergoing D2 lymphadenectomy chemo-radiation was associated with improved RFS. However, the therapeutic gains are not without increased toxicity.  In the McDonald's study, overall 75% incidence of grade III-IV toxicity was observed (gastrointestinal (GI) toxicity: 33% and hematological (HL): 42%). This led to poor treatment compliance with only 65% patients completing the planned chemo-radiation.  Poor compliance has been attributed to the large parallel opposed radiation fields used to cover the tumor bed and the regional lymph nodes. The use of three-dimensional conformal radiation (3DCRT) in earlier studies has also been associated with >50% grade III acute GI toxicity. , Image Guided Intensity Modulated Radiotherapy (IG-IMRT) leads to preferential sparing of adjacent oragns at risk (OAR) and can potentially reduce toxicity. , However, comparative clinical outcomes using 3DCRT or IMRT are relatively few. ,, Given the increasing use of peri-operative or adjuvant chemotherapy after D2 lymphadenectomy, , it is unlikely that the two techniques will be compared within a randomized study. The present study was performed to compare toxicity, compliance, and therapeutic outcomes of two techniques.
| > Subjects and methods|| |
From January 2010 to August 2013, consecutive patients planned for adjuvant chemo-radiation either with 3DCRT or IMRT were included.
Those with negative surgical margins received one cycle of adjuvant capcetabine (1000 mg/m2 p. o. bid week1-2). This was followed by chemoradiation (week 4-9: 45 Gy/25 fractions/5 weeks with concurrent capacetabine 825 mg/m2 p. o. b. i. d) and another two cycles of systemic chemotherapy. In patients with heavy nodal burden (N2 or higher), oxaliplatin was added during systemic phase of chemotherapy. Those with positive surgical margins received upfront chemo-radiation followed by 3-4 cycles of systemic chemotherapy.
All patients were treated with either 3DCRT or IG-IMRT. The choice of treatment technique was made by patients and was based on availability of treatment slots and logistics to travel to another facility to receive IMRT. All patients underwent computed tomography (CT) simulation after overnight fasting. No oral contrast was used. Patients were positioned supine with knee rest and arms above the head. Intravenous contrast was injected and axial images obtained from the level of carina to L4/5 interspace at an inter slice distance of 5 mm. Clinical Target Volume (CTV) included pre-operative tumor bed, residual stomach, anastomosis, duodenal stump, and draining lymph node sites. CTV was uniformly expanded by 10 mm to generate Planning Target Volume (PTV). OAR contouring included kidneys, liver, spinal cord, heart, and lungs. All 3DCRT planning was performed on Eclipse workstation version 8.6. For 3DCRT a five-field plan was generated with beam angles, field weight, and wedges optimized individually. All plans were finalized by same radiation oncologist (RE). All IG-IMRT planning was performed on Tomotherapy (Tomotherapy Inc., Madison, WI) and finalized by the same radiation oncologist (SC). Patients in 3DCRT cohort underwent Electronic Portal Imaging or Cone Beam CT (CBCT) for verification. All patients of IG-IMRT were treated using daily Megavoltage Computerized Tomography (MVCT) imaging.
All patients were evaluated weekly for any treatment related toxicity. For patients undergoing 3DCRT the acute toxicity was assessed using Radiation Therapy Oncology Group (RTOG) criteria by the attending physician. For purpose of the present study all these scores were retrospectively converted into Common Toxicity Criteria for Adverse Event (CTCAE) vs 3.0 score. All patients undergoing IG-IMRT were evaluated weekly by trained nurse and symptoms were scored using CTCAE version 3.0.
Patients were scheduled for follow-up every 3 monthly for the first 2 years and 6 monthly thereafter. Late toxicities were recorded for all patients using CTCAE vs 3.0 during their follow-up visits or by telephonic interview. Toxicity recording was done till the time of relapse to prevent confounding effect of symptoms of recurrence or salvage treatment on assessment of toxicity.
At each follow-up abdominal imaging (CT scan or Ultrasonography) was requested and chest X-ray and blood biochemistry was performed. Patients presenting with symptoms of gastric outlet obstruction or with radiological evidence of local recurrence underwent endoscopic evaluation with biopsy. For patients presenting with ascites, fluid cytology was performed. Patterns of recurrence were categorized as local, distant, both local and distant, and unknown.
All statistical analysis was performed with Statistical Package for the Social Sciences (SPSS) version 16. An independent sample non-parametric t-test (Mann-Whitney U test) was used to exclude differences between the 3DCRT and IMRT cohort. All toxicity scores were categorized as grade 0-I and Grade II-V. The difference in toxicity during treatment was evaluated using Chi-square test. RFS and OS was calculated using Kaplan Meir Survival curves and log rank analysis was performed to see difference in the OS, RFS. A P value of less than 0.05 was considered statistically significant.
| > Results|| |
A total of 51 patients were treated. The median age was 54 years (25-74 years). Overall there were 35 males (68.6%) and 16 females (31.4%). Eleven patients (21.5%) had proximal stomach and gastro-esophageal junction tumors and 40 (78%) had body, antral, or pyloric tumors. A total of 27 (52.9%) and 24 (47.1%) patients had adenocarcinoma and signet ring cell carcinoma, respectively. Thirty patients (58.8%) underwent surgical resection within our institution and 21 (41.2%) were operated in other centers. Of these, 19 patients (37.3%) underwent D0/D1 dissection and 32 (62.7%) underwent D2 dissection. A vast majority of surgical resection performed in other institutions (16/21; 76%) were D0/D1. Overall four patients received neoadjuvant chemotherapy and received adjuvant chemoradiation either due to involved or close margins or poor response to neoadjuvant chemotherapy. The information on total number of dissected nodes was available in only 42/51 patients. A median of 18 nodes were dissected (1-50) and a median of 3 nodes were positive (0-21). Among those undergoing D2 dissection the median dissected nodes were 20 (3-50). The median lymph node positivity ratio was 0.25 (0-1.0). The overall yield was low in patients operated outside or those undergoing D2 dissection after neoadjuvant chemotherapy. On final histopathology 42/51 (82.3%) had T3/T4 disease and 39/51 (76.4%) patients were node positive. A total of 4 patients had involved resection margins (7.8%).
Matched pair analysis
Twenty-six patients (51%) were treated with 3DCRT and 25 patients (49%) received IG-IMRT. The median age of 3DCRT and IMRT cohort was 51.5 and 56 years, respectively. (P = 0.17). The difference in male to female ratio in 3DCRT and IMRT arm was nonsignificant (73%:27% vs. 64%:26%; P = 0.29). The detailed matched pair analysis for both the cohorts is depicted in [Table 1]. Overall no imbalance was identified in either cohorts such that comparison for toxicity, local control and overall survival could be undertaken in both the treatment arms.
|Table 1: Table depicting distribution of baseline tumor and treatment characteristics in 3DCRT and IG-IMRT cohort|
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Organ at risk doses
The median radiation dose to the PTV was similar in the both arms. However the dose to the OARs was different between 3DCRT and IMRT. The median dose to right kidney was 12.4 Gy and 7.1 Gy with 3DCRT and IMRT, respectively (P = 0.001). Similar trend was observed in doses to the left kidney (29 Gy vs 8.2 Gy; P < 0.001). The use of IMRT was associated with statistically non-significant increase in median liver dose (15 vs 18.5 Gy; P = 0.07).
Overall 47/51 patients (92.2%) could complete the planned chemo-radiation and adjuvant systemic chemotherapy. One patient could not tolerate the planned chemo-radiation and systemic chemotherapy due to poor nutritional status and the treatment had to be stopped at 21.6 Gy. Another patient developed malignant ascites while on radiation and treatment was concluded at 25.2 Gy. She was not offered any further systemic chemotherapy. One patient developed severe abdominal pain refractory to pain medications. After completing 39.6 Gy/22 fractions emergency re-exploration of abdomenwas performed due to acute abdominal pain. Intra-operatively bowel gangrene was identified secondary to mesenteric artery ischemia. This patient died within 24 hours of re-exploration. Another patient developed infield abdominal nodule at 41.4 Gy and radiation was interrupted for 10 days due to clinic-radiological suspicion of progression however biopsy of the nodule was unremarkable and patient proceeded to receive adjuvant systemic chemotherapy. Overall one patient had interruption of planned radiation for 10 days due to severe abdominal pain necessitating in patient admission and endoscopy. As endoscopy was unremarkable, patient was managed conservatively. One patient had Grade III thrombocytopenia on treatment necessitating interruption of concurrent capcetabine at mid-treatment. Another three patients developed ascites within 1-3 months of completion of chemo-radiation and did not proceed to receive adjuvant systemic chemotherapy.
The grades of toxicity at baseline (before initiating chemo-radiation and after 1 st cycle of chemotherapy), at completion of chemo-radiation, at 3 months and 6 months of chemo-radiation and follow-up is depicted in [Table 2]. Overall, 9/51 (17.6%) had grade II toxicity and 2/51 (3.9%) had grade III-V toxicity. While there was no difference in grade 0-I vs. grade II-V toxicity in both the study cohorts, a higher proportion of patients had grade II toxicity in the IMRT cohort. The median weight loss in IMRT cohort was 3.6 Kg (0.5-6 Kg). Weight loss information was missing in vast majority of patients undergoing 3DCRT.
|Table 2: Depicting grades of gastrointestinal toxicity in the two cohorts|
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Overall 19.6% (n = 10) patients developed grade II hematological toxicity and 5.9% (n = 2) patients developed grade III hematological toxicity during chemo-radiation. Among these, one patient had grade III toxicity due to lymphopenia and another one patient had grade III toxicity due to thrombocytopenia. In these patients concurrent capacetabine had to be stopped midway during treatment. The low lymphocyte and platelet counts recovered without need for transfusion or growth factors. Grade IV toxicity was observed in one patient in last week of chemo-radiation necessitating capacetabine cessation and platelet transfusion. The details of hematological toxicity and comparison between two treatment arms is depicted in [Table 3]. At 3 months after chemo-radiation three patients (5.8%) had grade III hematological toxicity. Of these, one patient had low white blood cell counts and another two had low platelets. Overall there was no difference in 3DCRT or IMRT arm.
At baseline, four patients had grade I derangement of serum creatinine and one patient had grade II derangement of serum creatinine. At the end of chemo-radiation, three patients had grade I derangement of serum creatinine. At 3 months, no patient had derangement in serum creatinine.
The median follow-up of the entire cohort was 17 months (4-49 months) and those for surviving and relapse free patients was 25 months (4-49 months). Only one patient in the 3DCRT cohort had grade III toxicity (vomiting). This patient relapsed 16 months after treatment with recurrence at port site along with distant metastasis. No obstruction was identified on endoscopy performed at the time of relapse. Two patients had grade II-IV HL toxicity at follow-up one each in 3DCRT and IMRT arm. None of the patients had derangements of renal function in either of the treatment arm.
The mean RFS and OS for the entire cohort was 19.3 months (4-49 months) and 20.4 months (4-49 months). The 3-year RFS was 40% and 39%, respectively in 3DCRT and IMRT arm (P = 0.68) and 3-year OS was 39% and 38%, respectively (P = 0.97) [Figure 1] [a and b]. There was low rate (11.7%; n = 6) of loco-regional recurrence (remnant stomach = 2, anastomotic = 2, nodal = 1, anastomotic, and nodal = 1)). Recurrences were equally distributed in 3DCRT and IMRT cohort (P = 0.14). A total of 22 patients had distant relapse with or without local recurrence (43.1%). Of these, 11/22 (50%) patients had relapse in peritoneum and 3/22 (13.6%) had relapse in liver. No significant effect of histology was observed on patterns of distant relapse. Univariate analysis for RFS and OS is depicted in [Table 4]. None of the factors were significant for relapse free survival. While lymph node ratio, type of lymph node dissection were identified as significant for predicting OS on univariate analysis [Table 4] on multivariate analysis only the use of D2 lymphadenectomy was associated with improved OS.
|Figure 1: (a) Relapse free survival in two treatment cohorts, (b) Overall survival in two treatment cohorts|
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|Table 4: Univariate analysis for relapse free and overall survival evaluating patient, pathology, and treatment-related factors|
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| > Discussion|| |
High precision treatment delivery with techniques like IMRT can theoretically reduce toxicity of upper GI radiation. However, IMRT is resource intensive and requires stringent quality assurance.  Given the reports of dosimetric superiority of IMRT over 3DCRT , we designed this study to compare acute toxicity, patterns of relapse and late toxicity in patients undergoing 3DCRT and IMRT. To minimize bias between two cohorts we performed a matched pair analysis to exclude any sources of potential baseline bias. As seen in [Table 1] both cohorts were well matched for baseline factors.
We observed overall low incidence of grade III/IV GI (3.9%) and HL (6.3%) toxicity therefore the compliance to adjuvant chemo-radiation and chemotherapy was higher (92.2%) than that reported with the use of parallel opposed radiation technique in McDonald's (65%)  and ARTIST (81.7%) study  or to adjuvant chemotherapy within MAGIC (42%),  CLASSIC (67%),  and ARTIST study (75.4%).  This was also higher than the compliance rates of 50-67% reported with the use of 3DCRT. , Earlier series using conformal radiation (3DCRT) continued to report high incidence of grade III GI and HL toxicity as in one study investigators did not reduce the 5 Fluorouracil (5FU) dose during the concurrent phase (as in INT 0116) and used increasing doses of cisplatin which could have increased the incidence of grade III toxicity. , The other 3DCRT study used combination of capacetabine and oxaliplatin rather than 5FU alone which could have increased the acute toxicity. , The favorable toxicity and compliance rates observed in the present study are however similar to that observed rates with recent 3DCRT and IMRT studies (92.6-93.5%). 
On matched pair analysis we observed no difference in acute Grade II-V GI or HL toxicity with either technique. On the contrary we observed a statistically non-significant increase in Grade II toxicity within the IMRT cohort. While a real increase in grade II toxicity in IMRTdue to low dose spillage cannot be ruled out, this could possibly be attributed to retrospective conversion of RTOG into CTCAE score within the 3DCRT cohort. RTOG bowel toxicity scoring is known to underestimate grade I-II GI toxicity even during prospective recording of toxicity. 
Three studies have compared 3DCRT and IMRT for toxicity and outcomes. A German study  reported on outcomes of 27 and 33 patients treated with 3DCRT with 5FU-Folinic Acid (2001-2005) and IMRT (with 5FU/Folinic Acid or 4 cycles of Capcetabine/oxaliplatin combination (2005-2007)). Authors reported grade III GI toxicity rate of 57% and grade III HL toxicity of 10%. This high rate of GI toxicity could possibly be attributed to use of increased number of cycles of capcetabine and oxaliplatin. While comparative acute toxicity data is not reported for two cohorts, there was no difference in late toxicity between 3DCRT or IMRT. However improvement in overall survival was observed with use of capacetabine, oxaliplatin, and IMRT (67% vs 37% P = 0.04).
Another North American study  compared 3DCRT and IMRT for adjuvant gastric chemo-radiation in 61 patients. With a compliance rate of 93.5%, Grade III GI toxicity was observed in 15% and 16% patients in 3DCRT and IMRT cohort. There was no difference in local control (83% and 81%, P = 0.9), 2-year RFS (60% vs 54%, P = 0.80) or 2-year OS (51% and 65%, P = 0.50) between the two cohorts. The locoregional failure rate was 15% and 13%, respectively. Another small study of 24 patients from North America recorded grade III GI toxicity of 8.3% each in 3DCRT and IMRT arm.  No late grade III toxicity was observed in either cohort. The 3 year DFS and OS was 41% and 40%, respectively with no difference in the study cohort.
The present study reports matched pair analysis of patients receiving 3DCRT and IMRT. In our set-up, the compliance of adjuvant chemo-radiation using 3DCRT or IMRT is high and comparable to other centers using IMRT. The local recurrence rate of 11.7% is similar to other groups using 3DCRT and IMRT. We recorded a 3-year OS of 39% that is comparable to patients treated in North America outside the setting of a clinical trial.
While adjuvant chemoradiation can be used with high compliance and low toxicity within our population, a vast proportion of patients in our study, and in other reported studies have high rate of distant failure in-spite of using systemic therapy. We observed distant relapse rate of 43.1% and 50% of these relapses were observed in peritoneum. Given that the vast majority of patients succumb to distant (or peritoneal) metastasis inspite of systemic chemotherapy, it would be prudent to investigate other strategies of decreasing peritoneal recurrences. Whole abdominal radiation therapy (WART), employed in the management of other cancers with high peritoneal failure rates (like ovarian cancer)  and outcomes of which have been reported for gastric cancer  needs systematic prospective systematic investigation for adjuvant treatment of high risk gastric cancers.
| > Conclusions|| |
A vast majority of patients with gastric cancer in the present study had distant relapse. Though we could not identify any difference between 3DCRT and IMRT cohort it is also likely that the high distant failure rate and censoring for toxicity evaluation at relapse precluded assessment of real difference between two techniques if any. High rates of peritoneal failure in patients with post-operative high risk features inspite of intensive systemic chemotherapy necessitates investigation of alternative strategies to reduce treatment failure.
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[Table 1], [Table 2], [Table 3], [Table 4]