TURKISH JOURNAL OF ONCOLOGY 2019 , Vol 34 , Num 4
Radiotherapy Technique can be Important on Survival in Patients with Gastric Cancer Treated with Postoperative Chemoradiotherapy
Beyza Şirin ÖZDEMİR1
1Department of Radiation Oncology, Akdeniz university, Antalya-Turkey DOI : 10.5505/tjo.2019.1995

Summary

OBJECTIVE
This study aims to investigate the clinical and pathological features of gastric carcinoma and to evaluate the survival of the patients with gastric carcinoma receiving postoperative chemoradiotherapy.

METHODS
In this study, two hundred and four patients who received postoperative chemoradiotherapy for gastric cancer in our clinic from 1999 to 2014 were evaluated retrospectively. Clinical prognostic factors affecting survival were studied.

RESULTS
The median follow-up period was 30.52 months. Overall survival time was 80.47±5.04 months, and the 5-year survival rate was 47.0±4.1%. Overall disease-free survival (DFS) time was 84.58±5.38 months. A lower number of dissected lymph nodes and a higher number of metastatic lymph nodes were found to be related to increased risk of death and also a higher risk for recurrence. Stage 3 cancer was found to have a higher recurrence risk than stage 1 and 2. Recipients of three-dimensional conformal radiotherapy (3DCRT) treatment had a lower risk of death compared to the patients that received 2D treatment.

CONCLUSION
Postoperative chemoradiotherapy should be considered for all the patients with a high risk of recurrence after gastrectomy. In addition to the well-known prognostic factors, such as stage, lymph node metastasis, lymphatic dissection type, radiotherapy technique, was also found to be an important prognostic factor in our study. These results suggest that there is a long-term survival benefit for the patients treated with 3DCRT.

Introduction

Gastric cancer (GC) is one of the most common malignancies worldwide. The incidence of gastric cancer varies in different geographic regions. The highest incidence rates are in Eastern Asia, the Andean regions of South America, and Eastern Europe, while the lowest rates are in North America, Northern Europe, and most countries in Africa and South-Eastern Asia. There is also a substantial difference in the incidence among different ethnic groups within the same region.[1,2] Despite recent improvements in therapeutic methods, gastric cancer still has high mortality rates, in part due to the asymptomatic nature of the disease, rewhich causes the majority of patients with gastric cancer to be diagnosed at an advanced stage.[3] Despite this, Asian gastric cancer patients have a better prognosis than Western patients, probably due to an active screening program or to a more aggressive therapeutic approach.[4,5]

Surgery remains the only curative therapy in gastric cancer, while perioperative and adjuvant chemotherapy, as well as chemoradiation have been shown to improve outcomes in patients who undergo surgical resection with extended lymph node dissection.[6] The high rate of local-regional recurrence after resection is the main factor accounting for mortality. Therefore, it is important to consider adjuvant treatment in gastric cancer. For patients with stage Ib-IV with M0 gastric cancer, postoperative radiotherapy (RT) plus concurrent chemotherapy (CT) is recommended.[3,4] Because of the critical organs in the vicinity, the planning of RT in gastric cancer is crucial for sufficient treatment without severe side-effects.[7] Furthermore, as local-regional failures occur commonly within the gastric bed, regional lymph nodes and the anastomosis line, these areas should also be covered in the RT field. Target volumes for irradiation are defined based on the site, T-stage, and N-stage of the primary tumor. With the advances in radiotherapy techniques, twodimensional radiotherapy (2DRT) has been replaced with 3-dimensional conformal radiotherapy (3DCRT), while the intensity-modulated radiotherapy (IMRT) technique has also emerged as an option. These modalities are recognized for their ability to reduce complication rates.[8]

Many studies have shown that lymph node metastasis is the most important prognostic factor in gastric cancer.[9-11] Other prognostic factors in gastric cancer are the presence of distant metastases, lymphatic dissection type, tumor size, localization, histological type, stage, macroscopic type and depth of invasion. [12-14] Radiation therapy affects the prognosis by exhibiting significant survival benefit in patients with gastric cancer.[15] However, data in this field are limited, and there is currently no consensus as to the advantages and limitations of various modalities used as adjuvant therapy in patients who have undergone surgery for gastric cancer. Therefore, to contribute to the relevant literature, in this study, we investigated the clinical-pathological features, the prognostic factors, the survival rates and the importance of radiotherapy techniques in patients with gastric carcinoma receiving postoperative chemoradiotherapy.

Methods

Study group
In this study, two hundred and four patients who received postoperative chemoradiotherapy for the diagnosis of gastric cancer in the Department of Radiation Oncology, Akdeniz University School of Medicine from 1999 to 2014 were evaluated retrospectively. Ethical approval was obtained. The current study was conducted according to the principles put forth by the Helsinki Declaration and Good Clinical Practice guidelines.

Measurements
Clinical prognostic factors affecting survival were studied. Pre-treatment evaluation consisted of computed tomography (CT) or 18F-fluorodeoxyglucose positron emission tomography (PET-CT), which were performed on all patients for the purpose of staging. All patients underwent surgery. EBRT was delivered to a total dose of 40-54 Gy (median 46 Gy) in 1.8-2 Gy fraction doses using 10-25 MV X-rays. Until June 2009, two-dimensional conventional radiotherapy (2DRT), after that, the three-dimensional conformal radiotherapy technique (3DCRT) was performed.

For planning with the 2DRT technique, an X-Ray (conventional) simulator was used and performed with intravenous and oral contrast for delineating structures of interest. Parallel-opposed anteroposterior (AP)- poster anterior (PA) fields or a four-field box technique (anterior-posterior (AP)-posterior-anterior (PA)-2 lateral) were the most practical arrangements.

As for planning the 3DCRT technique, computed tomography (CT) simulation images of the patients were taken (adjacent axial slice spacing 2.5 mm; GELightspeed64 ® computed tomography simulator, GE, Fairfield, USA) with intravenous contrast. The target volumes and critical normal tissues (bowel, liver, kidneys, spinal cord) were outlined on each CT slice. 3DCRT with AP- PA- 2 lateral plus 3 or 4 segments were employed. Lateral fields and segments were used as a component of treatment to spare liver, spinal cord and heart tissues.

Clinical target volume (CTV) included the gastric remnant, anastomosis and stump, tumor bed, regional lymphatics (perigastric, porta hepatis, celiac, suprapancreatic, superior mesenteric, pancreaticoduodenal, splenic hilum) at risk based on sites of adherence of the primary lesion in each of the patients. For planning target volume (PTV), a margin of 1cm was added to CTV in all directions. Most of the patients (92%) received 5-fluorouracil (5-FU)-based chemotherapy during radiotherapy (RT).

All analyses in this study were performed in SPSS v21. Survival analyses were conducted with the Kaplan- Meier method. Survival and recurrence time comparisons between groups were evaluated using the Log-Rank test. Pairwise comparisons were made with the Bonferroni correction method. the effects of continuous and categorical variables on survival and recurrence were evaluated with Cox regression analysis with the backward conditional method. p?0.05 values were accepted as statistically significant.

Results

We included 204 patients (129 male and 75 female) in our study. The mean age was 56.51±11.35 years. Median follow up time was 30.52 months, and maximum follow up time was 149 months. Most of the patients had stage 3 cancer (67.8%), the most common histologic type was mucinous carcinoma (72.1%), 76 (37.3%) patients had received total gastrectomy while 128 (62.7%) had subtotal. Twenty-nine (14.3%) patients had hematologic toxicity above grade 3, 11 (5.4%) patients had nonhematologic toxicity above grade 3, and 2 of them had passed away because of toxicity. Seventy-nine (40.3%) patients had a recurrence while 14 (%6.9) patients had local metastasis, and 65 (31.9%) patients had distant metastasis. At the end of this study, 83 (40.7%) patients were alive without disease, 6 (2.9%) patients were alive with disease. During this study, 94 (46.1%) patients died due to cancer, while 21 (10.3%) patients died due to other causes.

Overall survival time was 80.47±5.04 months, and the 5-year survival rate was 47.0±4.1%. N2, N3a and N3b cancers had significantly lower survival times than N0 and N1 (p<0.001). Mean survival time was 65.53±5.87 months for stage 3 cancers, while it was 111.40±7.85 months for stage 1 and 2 cancers (p<0.001). Patients who underwent R1 resection had lower survival times than other patients (p=0.018). Five-year survival rate was 41.7±4.5 % for the patients who had D1 lymphatic dissection, while the five-year survival rate was 62.4±10.8% for the patients who had D2 lymphatic dissection (p=0.033). Patients with lymphatic metastasis had lower survival rates compared to the patients who did not (p=0.002). Patients who received 3DCRT treatment had higher 5-year survival rates than the patients who received 2DRT (p<0.001). Mean survival time was 34.48±3.88 months for the patients with recurrence, while the patients that did not have recurrence had a mean survival time of 129.09±4.70 months (p<0.001). Patients with metastasis had significantly lower survival times than patients who did not develop metastasis (p<0.001). However, there were no significant differences between patients with local and distant metastasis in terms of survival time (p=0.784). Concerning other parameters, there were no significant differences for survival times regarding gender, tumor location, differentiation, histologic type, surgery, chemotherapy treatment, radiotherapy dose, presence of toxicity, and presence of vascular, lymphatic or perineural invasion (Table 1).

Table 1: Survival times (months) with the Kaplan Meier method and comparisons of groups with long rank test for categorical variables

Table 1: Cont.

Overall disease-free survival (DFS) time was 84.58±5.38 months. N2, N3a and N3b cancers had significantly lower survival times than N0 and N1 (p<0.001). Mean DFS time was 70.70±6.48 months for stage 3 cancers, while in the patients with stage 1 or 2 cancers had a mean DFS time of 107.96±8.34 months (p<0.001). Patients with lymphatic metastasis had lower DFS times than the patients who did not (p=0.014). There were no significant differences between patients with local and distant metastasis (p=0.690). Also, there were no significant differences for DFS times regarding gender, tumor location, differentiation, histologic type, surgery, resection type, lymphatic dissection type, radiotherapy type and dose, presence of toxicity, and the presence of vascular, lymphatic or perineural invasion (Table 2).

Table 2: Disease free survival times (months) with the Kaplan Meier method and comparisons of groups with long rank test for categorical variables

Table 2: Cont.

Cox regression analysis was performed to determine factors that were effective on survival, including factors, such as age, dissected lymph node count, metastatic lymph node count and other significant categorical variables. We found that higher age (p=0.032), lower number of dissected lymph nodes (p=0.044) and a higher number of metastatic lymph nodes (p<0.001) were related to the increased risk of death. Also, patients with stage 3 cancer had 1.995-fold higher risk of death than the patients with stage 1 and 2 cancer (p=0.032), receiving 3DCRT treatment was found to cause 0.486-fold lower risk of death compared to 2DRT treatment (p=0.001), patients with local metastasis had 3.532-fold higher risk of death than the patients without metastasis, while patients with distant metastasis had 6.640 times higher risk of death compared to the patients without metastasis (p<0.001) The other variables we included in the analysis that were not found to be significant concerning survival were as follows: lymphatic metastasis (p=0.818), resection (p=0.293) and lymphatic dissection (p=0.175) (Table 3).

Table 3: Cox regression analysis results for survival times

Another Cox regression analysis was performed to determine factors that were effective on DFS; with age, dissected lymph node count, metastatic lymph node count and other significant categorical variables. We found that a lower number of dissected lymph nodes (p=0.007) and a higher number of metastatic lymph nodes (p<0.001) were related to increased recurrence risk. Also, stage 3 cancer was found to cause a 2.474-fold higher recurrence risk than stage 1 and 2 cancer (p=0.002). The other variables we included in the analysis, age (p=0.554) and lymphatic metastasis (p=0.775), were not found to affect DFS significantly (Table 4).

Table 4: Cox regression analysis results for disease free survival times

Discussion

Gastric cancer has a very poor prognosis and is still among the most important causes of death due to malignancy. The primary treatment for gastric cancer is surgery, but prognostic factors that determine local and regional recurrence after surgery also determine the need for adjuvant therapy.[16] A study had shown that three-year overall and disease-free survival time was significantly better for patients receiving chemoradiotherapy in addition to postoperative chemotherapy.[15]

Studies have shown that, excluding early stomach cancers and results from Japan, 5-year survival in gastric cancer is 25-40%.[17,18] In this study, it was found mean overall survival time of patients as 80.47±5.04 months, and 5-year survival rate was 47.0±4.1%, which was higher compared to the literature.

Lymph node metastasis is accepted to be one of the most important prognostic factors in cases of gastric cancer. Siewert et al., in their study, comprised of 1654 patients with gastric cancer, reported that the most important poor prognostic factor was lymph node involvement rate; the authors reported that an involvement rate higher than 20% had significantly shorter survival.[12] Similarly, in this study, patients with lymphatic metastasis had lower survival rates and lower DFS times than the patients who did not. Cox regression analysis for determining important factors on survival also showed that higher metastatic lymph node count was related to increased risk of death.

Adachi et al., in their comprehensive study on patients with gastric cancer, reported that the stage of the disease, the state of the lymph nodes and the degree of penetration of the tumor tissue in the stomach wall, were the most important factors effective on prognosis. In their study, the 5-year survival rate was 90% in stage IA, 80% in stage IB, 65% in stage II, 50% in stage IIIA, 30% in stage IIIB, and 5% in stage IV.[19] Similarly, Ersan et al. also found significant differences in mean survival (81.4%/27.1%) and 5-year survival (88.2%/3.7%) when patients with Stage I and IV cancer were compared in their study comprised of 154 patients with gastric cancer who underwent curative resection. [20] Similarly, in the present study, the mean survival times of stage 3 patients (65.53±5.87 months) was significantly shorter than the mean survival times of stage 1 and 2 (114.40±7.85) patients. Having stage 3 cancer resulted in a 1.995-fold higher death risk compared to stage 1 and 2 cancers. In addition, we found that survival time was shorter in patients with metastasis. Local metastasis caused 3.532-fold, and distant metastasis caused a 6.640-fold higher death risk compared to no metastasis. However, there was no statistically significant difference concerning survival between those with local and distal metastasis.

In the literature, some studies have reported high mortality and morbidity rates for patients undergoing D2 dissection.[21,22] However, Ron Lavy et al. reported that mortality and morbidity rates were not high for D2 lymphadenectomy. In addition, they recommended D2 dissection as the standard approach. [23] In another study, it was reported that patients with N+ tumors and pT 2-4 tumors with LN involvement in the D1 arm, had 5-year OS rates of 43% and 35%, respectively.[24] In this study, most of the patients had lymph node metastasis (pN+) and locallyadvanced stage (pT2-4). Furthermore, most of the patients had undergone D1 dissection, with a dissected lymph node count of 10 or less. However, results were fairly consistent with the literature. In this study, only 14% of the patients had undergone D2 dissection; however, the 5-year survival rate with D2 dissection (62.4±10.8%) was better than that of the patients with D1 dissection (41.7±4.5%). In terms of age, Gaito et al., in their retrospective study of 1473 gastric cancer patients who underwent curative resection, reported that age is an independent prognostic factor.[25] Our results also showed that higher age was related to increased death risk, confirming this finding.

The use of postoperative combined chemotherapy was suggested to become the standard for patients with locally advanced stage cancer in a study by Macdonald et al. Although this study demonstrated a significant survival benefit, toxicity rates were high. The main reason for high toxicity may have been the use of the 2DRT technique.[3] Therefore, the radiation characteristics of methods were put to the question; however, to our knowledge, there were very few studies that could demonstrate an approach that could reduce toxicity. In one study, it was emphasized that parallel-opposed anteroposterior-posteroanterior fields (AP-PA technique) were the most practical approach in 2D planning because, with this method, the kidneys could be spared from irradiation.[26] In 2014, a study compared conformal and conventional radiotherapy techniques in 36 patients dosimetrically. Dose homogeneity and doses of the organs at risk (left kidney and spinal cord) were found to be significantly improved by 3DCRT. Therefore, the authors suggested that the 3DCRT method may be beneficial in tumor control while also reducing complications in normal tissues.[27] Similarly, in the current study, we showed that the radiotherapy technique was an important prognostic factor for gastric cancer, and patients receiving 3DCRT were found to have superior survival rates.

To our knowledge, our study is the first in the relevant literature comparing the 3DCRT and 2DRT techniques concerning survival and toxicity in patients with gastric cancer. In light of our results, we believe that the 3DCRT technique provides better results compared to 2DRT. However, our study was retrospective in design and our findings require confirmation through randomized clinical trials involving a higher number of patients. Another limitation of this study is that there was a time-bound difference in the use of 2DRT and 3DCRT, which may have contributed to the difference between the two methods. Furthermore, the effects of advances in other treatment parameters and patient care (from 1999 to 2014) were not evaluated and may have caused differences in patient survival.

Conclusion

In this study, this study aimed to evaluate the results of chemoradiotherapy concerning survival rates and prognostic factors in gastric carcinoma patients who underwent surgical resection. We found that higher age, lower dissected lymph node count, higher metastatic lymph node count, cancer stage (3 vs. 1 and 2), and radiotherapy technique (3DCRT vs 2DRT) are significantly associated with prognosis. We believe that novel technological developments in the field of radiotherapy and their advantages require frequent evaluation and constant research to determine their clinical utility.

Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

Financial Support: None declared.

References

1) Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(2):69-90.

2) Wong BC, Ching CK, Lam SK, Li ZL, Chen BW, Li YN, et al. Differential north to south gastric cancer-duodenal ulcer gradient in China. China Ulcer Study Group. J Gastroenterol Hepatol 1998;13(10):1050-7.

3) Steg PG, James SK, Atar D, LP Badano, CB Lundqvist, MA, Borger, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). European Heart Journal 2012;33: 2569-619.

4) Strong VE, Song KY, Park CH, Jacks LM, Gonen M, Shah M, et al., Comparison of gastric cancer survival following R0 resection in the United States and Korea using an internationally validated nomogram. Ann Surg 2010;251:640-6.

5) Bollschweiler E, Boettcher K, Hoelscher AH, Sasako M, Kinoshita T, Maruyama K, et al. Is the prognosis for Japanese and German patients with gastric cancer really different? Cancer 1993;71:2918-25.

6) Nashimoto A, Akazawa K, Isobe Y, Miyashiro I, Katai H, Kodera Y, et al. Gastric cancer treated in 2002 in Japan: 2009 annual report of the JGCA nationwide registry. Gastric cancer 2013:16:1-27.

7) Joseph M Pepek, Junzo P Chino, Christopher G Willett, Manisha Palta, Dan G Blazer III, Douglas S Tyler, et al. Preoperative chemoradiotherapy for locally advanced gastric cancer. Radiat Oncol 2013;8:6.

8) Pang, X, Wei W, Leng W, Chen Q, Xia H, Chen L, et al. Radiotherapy for gastric cancer: a systematic review and meta-analysis. Tumour Biol 2014;35(1):387-96.

9) Santiago JR, Munoz E, Marti M, Quintana S, Veloso E, Marco C. Metastatic lymph node ratio as a prognostic factor in gastric cancer. Eur J Surg Oncol 2005;31(1):59-66.

10) Ding YB, Chen GY, Xia JG, Zang XW, Yang HY, Yang L, et al. Correlation of tumor-positive ratio and number of perigastric lymph nodes with prognosis of patients with surgically-removed gastric carcinoma. World J Gastroenterol 2004;10(2):182-5.

11) Bando E, Yonemura Y, Taniguchi K, Fushida S, Fujimura T, Miwa K. Outcome of ratio of lymph node metastasis in gastric carcinoma. Ann Surg Oncol 2002;9(8):775-84.

12) Siewert, JR, Böttcher K, Stein HJ, Roder JD. Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 1998;228(4):449-61.

13) Maruyama, K. The most important prognostic factors for gastric cancer patients: a study using univariate and multivariate analyses. Scandinavian Journal of Gastroenterology 1987:22:63-8.

14) Hyung, WJ, Lee JH, Choi SH, Min J.S., Noh S.H. Prognostic impact of lymphatic and/or blood vessel invasion in patients with node-negative advanced gastric cancer. Ann Surg Oncol 2002;9(6):562-7.

15) Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Eng J Med 2001;345(10):725-30.

16) Landry J, Tepper JE, Wood WC, Moulton EO, Koerner F, Sullinger J. Patterns of failure following curative resection of gastric carcinoma. Int J Radiat Oncol Biol Phys 1990;19(6):1357-62.

17) Allgayer H, MM Heiss, Schildberg FW. Prognostic factors in gastric cancer. Br J Surg 1997;84(12): 1651-64.

18) Wu CW, Lo SS, Shen KH, Hsieh MC, Chen JH, Chiang JH, et al. Incidence and factors associated with recurrence patterns after intended curative surgery for gastric cancer. World J Surg 2003;27(2):153-8.

19) Adachi Y, Shiraishi N, Suematsu T, Shiromizu A, Yamaguchi K, Kitano S. Most important lymph node information in gastric cancer: multivariate prognostic study. Ann Surg Oncol 2000;7(7):503-7.

20) Ersan Y, Erturk S, Cicek Y, Temiz M, Dirican A, Doğusoy G. Mide kanserli hastalarda klinikopatolojik prognostik faktörler. Cerrahpaşa Tıp Dergisi 2003;34(1).

21) Schwarz RE, Smith DD. Clinical impact of lymphadenectomy extent in resectable gastric cancer of advanced stage. Ann Surg Oncol 2007;14(2):317-28.

22) Goto H, Tokunaga M, Sugisawa N, Tanizawa Y, Bando E, Kawamura T, et al. Value of splenectomy in patients with Siewert type II adenocarcinoma of the esophagogastric junction. Gastric Cancer 2013;16(4):590-5.

23) Lavy R, Hershkovitz Y, Chikman B, Shapira Z, Poluksht N, Yarom N, et al. D1 versus D2 Gastrectomy for Gastric Adenocarcinoma. Isr Med Assoc J 2015; 17(12):735-8.

24) Degiuli M, Sasako M, Ponti A, Vendrame A, Tomatis M, Mazza C, et al. Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer. Br J Surg 2014;101(2):23-31.

25) Saito H, Osaki T, Murakami D, Sakamoto T, Kanaji S, Tatebe S, et al. Effect of age on prognosis in patients with gastric cancer. ANZ J Surg 2006;76(6):458-61.

26) Baeza MR, Giannini TO, Rivera SR, González P, González J, Vergara E, et al. Adjuvant radiochemotherapy in the treatment of completely resected, locally advanced gastric cancer. Int J Radiat Oncol Biol Phys 2001;50(3) 645-50.

27) Adas YG, Andrieu MN, Hicsonmez A, Atakul T, Dirican B, Aktas C, et al. Comparison of 2-dimensional and 3-dimensional conformal treatment plans in gastric cancer radiotherapy. Asian Pac J Cancer Prev 2014;15(17):7401-05.