|Year : 2014 | Volume
| Issue : 8 | Page : 267-271
Concurrent involved-field radiotherapy and XELOX in gastric cancer patients with postoperative oligometastatic recurrence
Cuiping Xu1, Jian Xie1, Ning Liang1, Junrong Wang2, Lili Qiao1, Hui Luo3, Jing Xin Zhang3, Jiandong Zhang1
1 Department of Radiation Oncology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, China
2 Department of Immunization Program, Shizhong Center for Disease Control and Prevention, Jinan, China
3 Department of Graduate, Division of Oncology, Weifang Medical College, Weifang, China
|Date of Web Publication||17-Feb-2015|
Department of Radiation Oncology, Qianfoshan Hospital Affiliated to Shandong University, 16766 Jingshi Road, Jinan, Shandong 250014
Source of Support: None, Conflict of Interest: None
Purpose: The aim of this study was to retrospectively observe gastric adenocarcinoma patients with postoperative oligometastatic recurrence and investigated the effects of concurrent involved-field radiotherapy (RT) and XELOX on progression-free survival (PFS).
Patients and Methods: From 2008 to 2011, 246 patients underwent curative resection of gastric carcinoma was enrolled. A retrospective review was performed on 34 patients with distant recurrence. Among them, 19 patients were oligometastases patients, where 13 patients received involved-field RT with a dose of 40-60 Gy by an intensity-modulated RT technique and concurrent XELOX chemotherapy, four patients were treated with XELOX chemotherapy alone (oxaliplatin 130 mg/m 2 , capecitabine 1000 mg/m 2 , twice daily, 3 week each cycle), and two patients with only brain metastasis were not included in the analysis.
Results: The median PFS was 11 months in the 13 oligometastatic patients who received concurrent involved-field RT and XELOX. The oligometastatic patients receiving concurrent radiochemotherapy trended toward a better median PFS when compared with those receiving chemotherapy alone.
Conclusions: For patients with postoperative oligometastatic recurrence, concurrent involved-field RT and XELOX showed better responses and was a choice for first-line treatment.
Keywords: Gastric cancer, oligometastatic recurrence, radiochemotherapy, XELOX
|How to cite this article:|
Xu C, Xie J, Liang N, Wang J, Qiao L, Luo H, Zhang JX, Zhang J. Concurrent involved-field radiotherapy and XELOX in gastric cancer patients with postoperative oligometastatic recurrence. J Can Res Ther 2014;10, Suppl S4:267-71
|How to cite this URL:|
Xu C, Xie J, Liang N, Wang J, Qiao L, Luo H, Zhang JX, Zhang J. Concurrent involved-field radiotherapy and XELOX in gastric cancer patients with postoperative oligometastatic recurrence. J Can Res Ther [serial online] 2014 [cited 2020 Oct 25];10:267-71. Available from: https://www.cancerjournal.net/text.asp?2014/10/8/267/151487
| > Introduction|| |
Gastric carcinoma is one of the most common malignancies worldwide. It has been the second leading cause of cancer-related death worldwide,  and its incidence and mortality continue to increase in China. Although neoadjuvant and adjuvant treatment has been used in managing of this type of disease, surgical resection remains as the key strategy of the treatment for gastric carcinoma. , Currently, radiotherapy (RT) has played a crucial role in the treatment of both operable and inoperable gastric carcinoma. According to the phase III trial INT0116 (SWOG 9008),  adjuvant concurrent radiochemotherapy (CRT) being adopted as a commonly used therapy for patients with curatively resected gastric cancer, which changed clinical practice in the United States. Unfortunately, despite curative resection combined multidisciplinary treatment, patients with advanced gastric cancers still have 21.8-49.5% recurrence. ,, The recurrence significantly reduces the patient's survival hopes. The majority of gastric cancer recurrences after curative resection occur within the first 2 years. , The median overall survival (OS) is estimated to be 1 year for recurrent gastric cancer used chemotherapy.  For recurrent gastric cancer patients, achievement of recurrence control to further improve results remains a substantial difficulty.
Palliative chemotherapy is general accepted to have a clear impact on survival for patients of metastatic stage IV malignancy. However, no chemotherapy regimen is considered as a standard solution until now, , and thus, the choice of chemotherapy depends on the patient's specific information. In patterns of the recurrence, loco-regional recurrence, hematogenous metastases, and peritoneal seeding were reported as a major pattern for recurrent gastric cancer patients. , For gastric cancer patients with postoperative loco-regional recurrence, we previously reported a study indicating that concurrent involved-field RT and XELOX showed better responses and overall symptom-control rates.  In our further analysis, we found a portion distant metastases referred to as oligometastases, which were limited in both number and organ with or without loco-regional recurrence. Now, among oligometastases patients, RT has been successfully used in medical treatment as local therapy. 
However, there have no studies that specifically investigated oligometastases in patients treated with RT for recurrent gastric cancer patients.
In this article, we retrospectively reviewed oligometastases gastric cancer patients with or without loco-regional recurrence and investigate the effects of concurrent involved-field RT and XELOX on the progression-free survival (PFS).
| > Patients and methods|| |
To evaluate the effects of CRT for oligometastases in patients with gastric chemotherapy, we reviewed a prospectively database with gastric adenocarcinoma and postoperative recurrence between January 2008 and December 2011. A total of 246 gastric carcinoma patients who underwent curative resection were identified in the database of our hospital. Finally, we identified 156 consecutive patients with postoperative recurrence. The first documented recurrence were localized to single site in loco-regional of 55 patients, distant of 22 patients, peritoneal recurrence of 32 patients and two sites in 37 patients, and three or more sites in 10 patients. A total of 34 patients with distant metastases were enrolled in this study, where 22 patients were single site, 12 patients recurrent in two sites. The patterns of first recurrence are described in [Table 1].
| > Follow-Up and Recurrence|| |
Patients were followed up every 3 months in the first 3 years, every 6 months in the thereafter. Follow-up evaluation consisted of physical examination, blood test, computed tomography (CT) scans of the abdomen, endoscopy and other necessary evaluation based on the patient's symptoms. Bone scans and brain magnetic resonance imaging was performed only when other tests were positive. On the whole, histological diagnosis confirmed when feasible and endoscopy was used for the diagnosis of recurrence in the anastomosis and gastric remnant.
Disease recurrence at the anastomotic or gastric remnant recurrence and nodal recurrence in the porta hepatis, celiac axis, superior mesenteric artery/vein, para-aortic, or gastrohepatic nodal regions was considered a loco-regional recurrence. Peritoneal recurrence involved the acolorectum, ovary, peritoneum, and ureter. All other sites of recurrence, including the liver, lung, bone, ovary, spleen, testis, or other distant organs, were considered distant recurrences. , One diagnostic radiologist evaluated recurrence according to the criteria of Japanese Classification of Gastric Carcinoma (JCGC). Research on this topic "oligometastases" disease refers to a limited metastatic burden was defined as distant metastases ranging from one to three, which will benefit from definitive RT, and so distant recurrence more than three metastatic lesions was consider as "polymetastases". ,
The aim of this study was to investigate the effects of concurrent involved-field RT and XELOX on PFS after recurrence. The Kaplan-Meier estimator was used to analyze the PFS. PFS was calculated from the date of recurrence to the date of objective disease progression. CT imaging was used to measure the tumor. Progression of disease was defined according to the criteria of JCGC. All of the statistical analysis was performed using the SPSS version 13.0 statistical software package (SPSS, Chicago, IL, USA).
| > Results|| |
In regard to the 34 patients with distant metastases, oligometastatic disease was found in 19 patients. We excluded two patients with only brain metastasis of those oligometastatic patients, because RT has been considered as the standard therapy for brain metastasis patients. The clinical characteristics of the 17 oligometastases patients in comparison with those of 15 polymetastatic patients were shown in [Table 2]. The location of recurrence in 17 oligometastases patients during the follow-up are displayed in [Table 3], include the livers in five patients, bone in three patients, lung in two patients, adrenal glands in one patient, extra-abdominal lymph nodes (LN) in one patient, bone and brain in one patient, bone and extra-abdominal LN in one patient, liver and lung in one patient, lung and extra-abdominal LN in one patient, and lung and brain in one patient.
|Table 2: Characteristics of the patients with postoperative distant recurrence|
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[Table 3] also describes the patient's therapeutic regimen. 13 oligometastatic patients were given involved-field RT using intensity-modulated radiotherapy technique (IMRT) techniques, two cycles of concurrent XELOX chemotherapy, and 2-4 cycles of XELOX chemotherapy after RT. RT was initiated on the 1 st day of chemotherapy. And other four patients only received four cycles of XELOX chemotherapy with oxaliplatin and capecitabine after the recurrences were diagnosed. A dose of 130 mg/m 2 Oxaliplatin was administered as a 2-h intravenous infusion on the 1 st day of each 3-week cycle. A dosage of 1000 mg/m 2 Capecitabine twice daily was administered orally according to the standard intermittent schedule.  IMRT with a dose of 40-60 Gy was used in involved-field RT patients using a linear accelerator with 6 MV photons. The dose was given in fractions of 1.8-2.0 Gy once daily, 5 times/week. All patients received treatments were well-tolerated without any treatment-related deaths.
The media PFS was 11 months (95% confidence interval [CI], 10.035-11.965) in the oligometastatic patients and 6 months in the polymetastatic patients (P < 0.05). The PFS curves after the treatment for recurrence is shown in [Figure 1]. Furthermore, the media PFS was 11 months in the oligometastatic patients who received concurrent involved-field RT and XELOX [Figure 2]. And the 4 oligometastatic patients who received XELOX chemotherapy was 5, 6, 8 and 10 months, respectively.
|Figure 1: The media progression-free survival (PFS) was 11 months (95% confidence interval, 10.035-11.965) in the oligometastatic patients and 6 months in the polymetastatic patients (P < 0.05). The PFS curves after the treatment for recurrence|
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|Figure 2: The media progression-free survival was 11 months in the oligometastatic patients who received concurrent involved-field radiotherapy and XELOX|
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| > Discussion|| |
Currently, surgical resection of the primary tumor and regional LN is the cornerstone of treatment of gastric cancer. , Nonetheless, the prognosis is poor and the incidence of recurrence is high for patients with curative resection.  The majority cases of postoperative recurrence of gastric cancer are loco-regional recurrence,  while the hematogenous metastases and peritoneal seeding were the next. For patients with recurrence, systemic chemotherapy is considered to really prolongs survival and improves the quality of life. However, effective treatment choices are still controversial. Our previous article found that the loco-regional recurrence from gastric cancer was sensitive to concurrent involved-field RT and XELOX and showed better responses and overall symptom-control rates.  We hold the opinion that distant metastases after curative resection is different from the initial clinical stage IV disease, especially for patients with oligometastases.
The purpose of the present study is to retrospectively evaluate the outcome of concurrent involved-field RT and XELOX in dvanced gastric cancer patients with postoperative oligometastatic on PFS. In this study, oligometastatic patients showed a relatively long media PFS (11 vs. 6, P < 0.05) compared with polymetastatic patients who received systemic CT. And also, the median PFS was 11 months in 13 oligometastatic patients who received concurrent CRT is longer than oligometastatic patients who receiver CT only. The media PFS of the 4 oligometastatic patients who refused to RT received XELOX chemotherapy alone was 6 months.
The landmark US Intergroup (INT) 0116 trial  demonstrated evidence of the effectiveness of CRT in the median overall survival from 27 to 36 months for gastric cancer. In the last decade, RT has been optimized with advances in radiation technology, especially the new technologies of stereotactic radiosurgery, image-guided RT or IMRT induced in therapy, which decrease the damage to normal tissues by accurately delivering the lethal arsenal of high dose radiation.  In a word, radiation therapy plays a key role in the treatment of gastric cancer. Recently, RT has become the new paradigm and options in the treatment of metastatic cancer, especially for the patients with oligometastases. 
Oligometastatic disease defines as a limited metastatic burden,  and often used to describe five or fewer metastatic lesions.  Hellman and Weichselbaum  for the first time put forward the concept of "Oligometastatic" in 1995, which was used to describe a relatively advanced state of metastatic disease and make a point of the feasibility with local therapy.
Until now, gastric cancer patients with recurrence after radical surgery still lack of effective salvage treatments, and the vast majority of postoperative recurrence is not suitable for surgery again. Kim et al. reported that RT to regional LN recurrence from gastric cancer lowered local recurrence.  The liver is one of the common sites of distant metastasis of gastric cancer, chemotherapy has been considered as the standard treatment. However, a single institution phase I-II study for primary and metastatic liver tumors achieved a 2-year local control of 86% and 2-year overall survival rates of 62% with SBRT,  which indicated RT was an effective treatment for patients with Oligometastatic in liver. In our research, we found concurrent CRT for patients with liver metastatic was well to tolerant, but whether the benefit in OS still needed continuous follow-up. Oligometastases of bone have been reported that RT provides long-term alleviated the pain and can even improve OS.  Sun et al.  concluded the RT was effective for abdominal LN metastasis in patients with recurrent gastric cancer and may prolong overall survival.
In summary, growing evidence demonstrated that concurrent CRT may help enhance local control for patients with postoperative oligometastatic recurrence. Our retrospective analysis found that concurrent involved-field RT and XELOX showed a palliative effect in PFS in gastric cancer patients with postoperative oligometastatic recurrence. Both our previous study  and the present study favor that patients with postoperative oligometastatic recurrence, concurrent involved-field RT and XELOX showed better responses and maybe a choice for first-line treatment. And that means many patients with limited recurrences still have curative hopes, active treatment is imperative to this population.
Although the results of this retrospective analysis are encouraging, and oligometastatic recurrence may propose different pathophysiologic mechanisms in a unique population, our study is not a randomized, controlled study and has several limitations. The number of patients included in the studies was relatively small, suggesting that interpretation of the cumulative estimates should be cautious. To further verify concurrent CRT can improve the survival of patients with oligometastatic recurrence, a prospective trial with a large sample size is needed.
| > References|| |
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet 2009;374:477-90.
Jansen EP, Boot H, Verheij M, van de Velde CJ. Optimal locoregional treatment in gastric cancer. J Clin Oncol 2005;23:4509-17.
Macdonald JS, Benedetti J, Smalley S, Haller D, Hundahl S, Jessup J, et al
. Chemoradiation of resected gastric cancer: A 10-year follow-up of the phase III trial INT0116 (SWOG 9008). J Clin Oncol; 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2009;Suppl:4515.
Lee SE, Ryu KW, Nam BH, Lee JH, Choi IJ, Kook MC, et al.
Prognostic significance of intraoperatively estimated surgical stage in curatively resected gastric cancer patients. J Am Coll Surg 2009;209:461-7.
Nurwidya F, Takahashi F, Takahashi K. Meeting report: Current cancer perspectives from the 9 th
Annual Meeting of the Japanese Society of Medical Oncology. Thorac Cancer 2012;3:94-7.
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;27:153-8.
Lai JF, Kim S, Kim K, Li C, Oh SJ, Hyung WJ, et al.
Prediction of recurrence of early gastric cancer after curative resection. Ann Surg Oncol 2009;16:1896-902.
Yokota T, Saito T, Teshima S, Yamada Y, Iwamoto K, Takahashi M, et al.
Early and late recurrences after gastrectomy for gastric cancer: A multiple logistic regression analysis. Ups J Med Sci 2002;107:17-22.
GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group, Oba K, Paoletti X, Bang YJ, Bleiberg H, Burzykowski T, et al.
Role of chemotherapy for advanced/recurrent gastric cancer: An individual-patient-data meta-analysis. Eur J Cancer 2013;49:1565-77.
Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: A systematic review and meta-analysis based on aggregate data. J Clin Oncol 2006;24:2903-9.
Rivera F, Vega-Villegas ME, López-Brea MF. Chemotherapy of advanced gastric cancer. Cancer Treat Rev 2007;33:315-24.
Yokoyama T, Kamada K, Tsurui Y, Kashizuka H, Okano E, Ogawa S, et al.
Clinicopathological analysis for recurrence of stage Ib gastric cancer (according to the second English edition of the Japanese classification of gastric carcinoma). Gastric Cancer 2011;14:372-7.
Eom BW, Yoon H, Ryu KW, Lee JH, Cho SJ, Lee JY, et al.
Predictors of timing and patterns of recurrence after curative resection for gastric cancer. Dig Surg 2010;27:481-6.
Yuan ST, Wang FL, Liu N, Liu YH, Liu SG, Huang Y, et al.
Concurrent Involved-field Radiotherapy and XELOX Versus XELOX Chemotherapy Alone in Gastric Cancer Patients With Postoperative Locoregional Recurrence. Am J Clin Oncol 2013; DOI: 10.1097/COC.0b013e31828f5cb6.
Macdermed DM, Weichselbaum RR, Salama JK. A rationale for the targeted treatment of oligometastases with radiotherapy. J Surg Oncol 2008;98:202-6.
Schwarz RE, Zagala-Nevarez K. Recurrence patterns after radical gastrectomy for gastric cancer: Prognostic factors and implications for postoperative adjuvant therapy. Ann Surg Oncol 2002;9:394-400.
Yano T, Okamoto T, Haro A, Fukuyama S, Yoshida T, Kohno M, et al.
Local treatment of oligometastatic recurrence in patients with resected non-small cell lung cancer. Lung Cancer 2013;82:431-5.
Badakhshi H, Grün A, Stromberger C, Budach V, Boehmer D. Oligometastases: The new paradigm and options for radiotherapy. A critical review. Strahlenther Onkol 2013;189:357-62.
Park YH, Lee JL, Ryoo BY, Ryu MH, Yang SH, Kim BS, et al.
Capecitabine in combination with Oxaliplatin (XELOX) as a first-line therapy for advanced gastric cancer. Cancer Chemother Pharmacol 2008;61:623-9.
Jain VK, Cunningham D, Chau I. Preoperative and postoperative chemotherapy for gastric cancer. Surg Oncol Clin N Am 2012;21:99-112.
Morabito A, Carillio G, Longo R. Systemic treatment of gastric cancer. Crit Rev Oncol Hematol 2009;70:216-34.
McCloskey SA, Yang GY. Benefits and challenges of radiation therapy in gastric cancer: Techniques for improving outcomes. Gastrointest Cancer Res 2009;3:15-9.
Niibe Y, Hayakawa K. Oligometastases and oligo-recurrence: The new era of cancer therapy. Jpn J Clin Oncol 2010;40:107-11.
Milano MT, Katz AW, Zhang H, Okunieff P. Oligometastases treated with stereotactic body radiotherapy: Long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys 2012;83:878-86.
Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8-10.
Kim BH, Eom KY, Kim JS, Kim HH, Park do J. Role of salvage radiotherapy for regional lymph node recurrence after radical surgery in advanced gastric cancer. Radiat Oncol J 2013;31:147-54.
Méndez Romero A, Wunderink W, Hussain SM, De Pooter JA, Heijmen BJ, Nowak PC, et al.
Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase I-II study. Acta Oncol 2006;45:831-7.
Milano MT, Zhang H, Metcalfe SK, Muhs AG, Okunieff P. Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy. Breast Cancer Res Treat 2009;115:601-8.
Sun J, Sun YH, Zeng ZC, Qin XY, Zeng MS, Chen B, et al.
Consideration of the role of radiotherapy for abdominal lymph node metastases in patients with recurrent gastric cancer. Int J Radiat Oncol Biol Phys 2010;77:384-91.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]