Results of adjuvant radiochemotherapy for gastric adenocarcinoma in Slovenia

EJSO 33 (2007) 982e987

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Results of adjuvant radiochemotherapy for gastric adenocarcinoma in Slovenia I. Oblak*, V. Velenik, F. Anderluh, P. Strojan Department of Radiotherapy, Institute of Oncology, Zalosˇka cesta 2, SI-1000 Ljubljana, Slovenia Accepted 12 December 2006 Available online 26 January 2007

Abstract Aims: To analyze the results of postoperative concomitant radiochemotherapy with 5-florouracil (5-FU) and leucovorin (LV) in patients with gastric carcinoma treated in a single institution. Methods: During 2001e2004, 123 patients with the mean age of 60 years, were treated for adenocarcinoma of the stomach, stage IbeIV, with postoperative concomitant radiochemotherapy. Radical (R0) and non-radical (R1) resection of the tumor was performed in 107 and 16 patients, respectively. Adjuvant treatment consisted of five cycles of five-day chemotherapy with 5-FU (425 mg/m2) and LV (20 mg/m2) and concomitant radiotherapy with the total dose of 45 Gy. Results: The treatment was completed according to the protocol in 101 patients. Stomatitis, dysphagia, and nausea and vomiting of grade three occurred in 32, 27, and 23 patients, respectively. The median follow-up time of 87 survivors was 30.4 months (range 17.4e58.3 months). At two years, locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) rates were 86%, 65%, 74%, and 73%, respectively. In the multivariate analysis, the initial Hb level was identified as independent prognostic factor for all survival four endpoints, the involvement of whole stomach with cancer for LRC, the total dose of 5-FU per five-day cycle for DFS, and pT stage for DSS. Conclusions: In operable gastric carcinoma, postoperative concomitant radiochemotherapy with 5-FU and LV is feasible and its toxicity acceptable. Its potential to improve the treatment outcome compared to the surgery alone is yet to be tested in well designed prospective randomized studies. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Gastric cancer; Adjuvant therapy; Radiochemotherapy; Survival; Toxicity

Introduction Gastric carcinoma is a disease with poor prognosis. At the time of diagnosis, two thirds of patients have locally and regionally advanced disease or systemic dissemination.1,2 In 30e50% of patients with gastric carcinoma, the cancer is non-resectable.3e5 The five-year survival of these patients is less than 10%.2 In the patients with resectable disease, the five-year survival after radical surgery only, is around 50%.3,6,7 The disease recurrence is observed in 75% of patients operated on, and in 40e65% of them, the disease recurred locally and/or regionally.2,5,8,9 A number of studies were carried out in order to improve the survival of the patients with resectable gastric carcinoma. As a result, postoperative treatment combining radiotherapy (RT) and chemotherapy (ChT), was established * Corresponding author. Tel.: þ386 1 587 9293; fax: þ386 1 587 8304. E-mail address: [email protected] (I. Oblak). 0748-7983/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2006.12.012

as a routine adjuvant therapy in USA, but is still under evaluation in Europe.3,9e14 In Slovenia, the program of combined postoperative treatment of non-metastatic gastric carcinoma with radiochemotherapy was introduced into clinical practice in 2001. This report presents the results of combined postoperative radiochemotherapy of the patients with resectable gastric carcinoma in Slovenia in the period 2001e2004. Patients and methods Patients In the period 2001e2004, 1880 patients with gastric adenocarcinoma were registered by the cancer Registry of Slovenia, which is the state’s central service for collecting and managing data on new cancer patients. At diagnosis, in 20% of patients the tumor was limited to the stomach, 38% had regionally advanced tumor and 31% had overt systemic

I. Oblak et al. / EJSO 33 (2007) 982e987

metastases (no data on the disease stage in 11% of patients). Eight-hundred and ten patients were operated on and 123 of them (79 males, 44 females; aged 31e76 years, mean age 60 years) were treated with postoperative concomitant chemoradiation at the Institute of Oncology Ljubljana, Slovenia. The criteria for selecting patients for adjuvant treatment after surgery were locally advanced (International Union Against Cancer [UICC] stage pT3 or pT415) tumors or node positive tumors, residual disease after surgery, World Health Organization (WHO) performance status 0e1,16 and absence of significant comorbidities. After surgery, all patients with the disease of pathological stage Ib or more were presented to a multidisciplinary advisory team, consisting of a surgeon, radiation oncologist and medical oncologist, in order to assess the prospects of eventual adjuvant treatment. All patients underwent a general clinical examination and blood counts. The patients with heart, liver or renal diseases and those with poor performance status (2 according to WHO) were assessed as non-eligible for adjuvant therapy. The investigations, such as X-ray, ultrasound (US), and/or computer tomography (CT) of the thorax or abdomen, made before surgery to rule out metastatic disease, were repeated only in the patients in whom the progression of the disease was clinically suspected. During the therapy, the patients were clinically examined and referred to hematology and biochemistry blood tests once a week. The therapy-related local and systemic toxicity was assessed according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0.17 Performance status of patients was determined and their body weight was measured on weekly basis.

Surgery Of the 123 patients, 104 were operated on in two major surgical centers in Slovenia, at the Maribor Teaching Hospital and University Medical Centre Ljubljana, and the remaining 19 patients in one of eight Slovenian regional hospitals. The decision on the local extent of resection depended on the results of preoperative investigations, intraoperative findings, and histological status of tumor margins as determined during surgery. Considering lymphadenectomy type, surgeons were supposed to follow the guidelines of the Japanese Research Society for the Study of Gastric Cancer which recommends D2 type of lymphadenectomy.18 Most frequently the primary tumor originated in the antrum (47 patients). In 75 patients, the tumor was staged as pT3 or pT4 (9 patients), and 119 patients had Nþ disease. Eighty-seven tumors were poorly differentiated (G3) (Table 1). Distal subtotal, total, and multivisceral resection of the stomach was performed in 50, 36 and 34 patients,

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Table 1 Pathohistologic characteristics of tumors Characteristics pT e stage 1 2 3 4 pN e stage 0 1 2 3 Overall stage Ib II IIIa IIIb IV Pathohistological tumor grade 1 2 3 unknown Borrmann type 1 2 3 4 unknown Growth type according to Lauren diffuse intestinal unknown Perineurial invasion yes no unknown Lymphovascular invasion yes no unknown Angioinvasion yes no unknown

No. of patients

%

9 39 66 9

7.3 31.7 53.7 7.3

4 53 42 24

3.3 43.1 34.1 19.5

6 26 37 24 30

4.9 21.1 30.1 19.5 24.4

5 25 87 6

4.1 20.3 70.7 4.9

4 14 43 24 38

3.3 11.4 35 19.5 30.9

61 55 7

49.6 44.7 5.7

59 45 19

48 36.6 15.4

66 23 34

53.7 18.7 27.6

23 45 55

18.7 36.6 44.7

pT, pathological T-stage; pN, pathological N-stage.

respectively, and three patients had resection of the carcinoma on gastric stump. In 92 patients, at least 15 lymph nodes were removed and histologically examined, and in 59 patients, the number of resected nodes was 25 or more; less than 15 lymph nodes were examined in 27 patients, while for four patients, no data were available. As determined on histopathological examination of surgical specimen, radical resection (R0, as defined by the UICC15) of the stomach was performed locally and regionally in 107 patients. In the remaining 16 patients who underwent non-radical surgery (R1, microscopic residual tumor), residual cancer was detected locally in eight patients, regionally in five patients, and locoregionally in three patients.

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Postoperative radiochemotherapy

Results

Adjuvant treatment was initiated six weeks after surgery and consisted of concomitantly applied ChT and RT. ChT included the following combination of cytostatics: 5-fluorouracil (5-FU) at a daily dose of 425 mg/m2 i.v. and leucovorin (LV) at a daily dose of 20 mg/m2 i.v., administered in bolus for five subsequent days. Treatment cycle was repeated every 28 days. During RT, the intensity of ChT was decreased. In the second and third cycle, only four and three applications of the drugs were administered, respectively. After RT, the patients received two more fiveday ChT cycles. Irradiation was applied during the second and third cycle of ChT. Patients were irradiated on linear accelerator with 5 MVe15 MV photon beams for five days per week, at a daily dose of 1.8 Gy. The total irradiation dose was 45 Gy delivered in five weeks. RT planning was performed using simulator with CT option and 2.5-D treatment planning computer software. Treatment field orientation was anteriorposterior. The primary tumor site and regional lymph node areas with a safety margin of 1.5 cme2 cm were irradiated and 2/3 of the ipsilateral kidney was protected using individual shielding blocks. Irradiation dose was specified according to the International Commission on Radiation Units (ICRU) recommendations. The position of individual irradiation fields was checked on weekly basis. In case of severe therapy-related toxicity, irradiation and/or ChT doses were modified and adopted to the patient’s physical condition or laboratory tests. When necessary, ChT application was delayed, or RT was temporarily interrupted or terminated.

Toxicity of adjuvant radiochemotherapy

Statistics Statistical analysis was performed using personal computer and software statistical package SPSS, version 12 (SPSS Inc., USA). The main endpoints of this study were as follows: locoregional control (LRC, the event was local and/or regional recurrence); disease-free survival (DFS, the event was local, regional or systemic recurrence); the disease-specific survival (DSS, the event was death due to gastric adenocarcinoma); and overall survival (OS, the event was death from any cause). The survival of patients was computed from the date of surgery to the May 1, 2006 (close-out date). Survival probability was calculated using KaplaneMeier estimate,19 and log rank test20 was used to evaluate the differences between individual groups of patients. Independent prognostic values of variables that appeared as statistically significant on univariate analysis were tested by multivariate Cox regression analysis model.21 Two-sided tests were used and the differences at p < 0.05 were considered as statistically significant.

Postoperative ChT started 3.6e11.9 weeks after surgery (median 5.9 weeks). In 93 patients adjuvant ChT was initiated according to the protocol, i.e. within six weeks after surgery. The reasons for the delayed initiation of adjuvant therapy in other 30 patients were perioperative complications with delayed wound healing or febrile episode (14 patients), radiotherapy waiting list (seven patients), delay in the presentation of the patient to the multidisciplinary advisory team (six patients), or additional diagnostic procedures performed to exclude suspected systemic dissemination (three patients). All five cycles of ChT were administered in 101 patients, 10 patients received four and 12 patients less than four ChT cycles. The duration of the RT part of the protocol ranged from 3.3 to 18 weeks (median 5.3 weeks). In 82 patients, irradiation was completed according to the protocol; three patients finished RT prematurely (one due to the disease progression during adjuvant treatment and two due to toxic side effects), whereas the prolongation of RT was recorded in 38 of patients. The median time of RT interruption was 22 days (range 1e60 days) and occurred due to treatment-related toxicity (16 patients; median duration 28.5 days, range 22e60 days) and machine breakdown (22 patients; median duration 5 days, range 1e22 days). One-hundred and twenty patients reached the total radiation dose of 45 Gy, whereas in three patients the total dose was lower (25.2, 27 and 32.4 Gy, respectively). Total postoperative treatment time ranged from 4.9 to 32.6 weeks (median 17.6 weeks). One-hundred and one patients completed the treatment according to the protocol (i.e. 45 Gy of RT and five cycles of ChT). No death occurred due to therapy. Acute toxicity, such as stomatitis, dysphagia, and nausea and vomiting of grade three, occurred in 32, 27, and 23 patients, respectively (Table 2). In nine patients, an increase of body weight was recorded during the therapy, four patients maintained constant weight, whereas the remaining 110 patients lost Table 2 Toxicity of adjuvant radiochemotherapy Toxicity

Stomatitis Radiodermatitis Diarrhoea Dysphagia Nausea, vomiting Infection Leucocyte count Hemoglobin level Platelet count

NCI grade (%)18 0

1

2

3

4

Total

48 95.2 79.7 44.7 56.9 50.4 30.1 19.5 92.7

10.6 1.6 5.7 12.1 11.4 18.7 29.3 70.7 7.3

15.4 1.6 5.7 21.2 13 18.7 30.1 9.8 0

26 1.6 8.9 22 18.7 12.2 9.7 0 0

0 0 0 0 0 0 0.8 0 0

100 100 100 100 100 100 100 100 100

I. Oblak et al. / EJSO 33 (2007) 982e987 100

their weight with respect to the weight they had at the beginning of treatment. The maximum body weight loss was 24.1% (mean 6.8%).

Prognostic factors On univariate analysis of survival patients with locally advanced disease (pT3e4), pN3-stage and overall disease stage IV had worse locoregional control and survival in comparison to their counterparts in all four survival endpoints. In addition, poor outcome of patients correlated 100

Survival (%)

80

60

40

20

Survival (%)

The median follow-up time of all 123 patients was 27.2 months (range 5.3e58.3 months), whereas in survivors it was 30.4 months (range 17.4e58.3 months). On the close-out date, 87 patients were still alive, 76 of them being with no signs of disease. Thirty-four patients died from gastric carcinoma, one patient who experienced locoregional recurrence and metastatic spread died from stroke, and in one patient the cause of death could not be determined. After adjuvant radiochemotherapy, recurrence was observed in 47 patients. Local and/or regional recurrence developed in five patients after a median period of time of 14.4 months (time range 9.7e18 months). Locoregional and systemic disease that developed in the median period of time of 11 months (time range 6.2e15.7 months) was observed in nine patients, and systemic disease alone developed in 33 patients in the median period of time of 13.9 months (time range 4.5e43.8 months). The two years follow-up survey showed that LRC, DFS, DSS and OS were 86%, 65%, 74%, and 73%, respectively, whereas the LRC and survival rates at three years were 86%, 55%, 65%, and 64%, respectively (Figs. 1 and 2). In the subgroup of 84 patients who had D2 lymphadenectomy and R0 resection, the corresponding rates at two years were 86%, 65%, 75% and 74%, respectively, and at three years 86%, 58%, 70%, and 68%, respectively.

80 60 40 20 DSS

0 0

12

24

36

48

60

48

60

Time (months) 100 80

Survival (%)

Treatment outcome and survival

985

60 40 20 OS

0 0

12

24

36

Time (months) Figure 2. Disease-specific survival (DSS) and overall survival (OS).

also with involvement of whole stomach with cancer (vs. involvement of individual stomach areas), tumor located in the cardia, vascular and perineurial invasion, low pretreatment hemoglobin (Hb) concentration (<110 g/l) and total 5-FU dose per five-day cycle of more than 4000 mg. None of the treatment-related factors (the length of the interval between surgery and adjuvant ChT, number of ChT cycles, duration of RT, total dose of RT, total postoperative treatment time) influenced any of survival endpoints analyzed in our group of patients. The multivariate analysis identified the initial Hb level 110 g/l as an independent prognostic factor for all four types of survival (LRC p ¼ 0.009, DFS p ¼ 0.0001, DSS p ¼ 0.02, OS p ¼ 0.01). Independent prognostic factor for LRC was the involvement of whole stomach with cancer ( p ¼ 0.05), for DFS the total 5-FU dose per five-day cycle of more than 4000 mg ( p ¼ 0.03) and for DSS pT-stage ( p ¼ 0.03).

LRC DFS

Discussion

0 0

12

24

36

48

60

Time (months) Figure 1. Locoregional control (LRC) and disease-free survival (DFS).

There is still a dispute on the survival benefit of adjuvant ChT alone (without concurrent RT) after curative resection for gastric cancer. The results of several meta-analyses of

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studies conducted in Europe, Asia and USA, were inconsistent regarding the survival advantage of adjuvant ChT.22e26 To the contrary, many authors proved that the combined RT and ChT with 5-FU may significantly improve the survival of these patients.3,9,27e30 The results of American intergroup study INT 0116 gave a powerful incentive for introducing postoperative radiochemotherapy as adjuvant treatment of patients with gastric carcinoma in routine clinical practice in USA as well as in a number of other countries. In this study, the comparison of 275 patients who had had surgery only with 281 patients who had been given adjuvant postoperative irradiation (TD ¼ 45 Gy) and ChT (5-FU in combination with LV) showed that the group treated with radiochemotherapy had significantly improved OS as well as LRC. The critics of American study claimed that the patients included in the study were not properly surgically treated because D2 lymphadenectomy was performed in only 10% of patients.9 We included 16 patients (13%) that on histopathological examination of surgical specimen were recognized as having had non-radical surgery. In some studies, this proportion was 15.5% and 20.5%, respectively.11,31 Furthermore, in our study the surgeons were obliged to follow the protocol and to perform routinely D2 lymphadenectomy according to the guidelines proposed by the Japanese Research Society for the Study of Gastric Cancer.17 Fifteen or more lymph nodes were removed and examined histologically in 92 of our patients whereas in 59 patients 25 or more lymph nodes were removed, which speaks in favor of adequately extensive lymphadenectomy. The other critique of the American intergroup study was referred to the high percentage of patients (36%) who did not conclude the therapy according to the protocol.9 Similarly, the Australians reported that, due to ChT related toxicity, the dose of the drugs had to be reduced in 48.9%, whereas in 24.5% patients the application of chemotherapeutics had to be delayed. The authors nevertheless believe that the INT 0116 protocol is safe and acceptable for clinical use31 and we also support this opinion. In our series as well as in Korean one,32 the major violations were recorded in substantially lower proportion of patients (18% and 21%, respectively). In our case, this favourable experience may be due to strict criteria used to select the patients for adjuvant therapy and the fact that we insisted on extensive advising of our patients on all potential side-effects of ChT and RT. Furthermore, to all of them, an intensive supportive care was also given. In regard to the efficacy of combined therapy, the INT 0116 study showed that the patients who were treated with postoperative radiochemotherapy had significantly better three-year OS (50% vs. 41%; p ¼ 0.005) as well as LRC (48% vs. 31%; p ¼ 0.001) than those who were only operated on.9 When relating these results with those of Korean study (three-year OS rate of 68% and relapse-free survival of 62%),32 the latter emerge as more favorable. As the same adjuvant regimen was used in

both studies, it seems that the reason for better outcome in Korean series is a more extensive lymphadenectomy. The interpretation of the results in our series could be delicate due to a shorter follow-up time of the patients and retrospective type of the study, considering all inherent limitations of such analysis. However, three-year OS and LRC of 64% and 86%, respectively, seem promising and add to the evidences of positive effect of postoperative radiochemotherapy. From our analysis of prognostic factors, we may conclude that the patients with larger tumors, involvement of numerous regional lymph nodes, tumor located in the cardia, perineurial and vascular invasion have poor survival. These factors are considered to be well established negative prognosticators in clinics and are also usually referred to in literature.30 Moreover, the subgroup of patients in whom distal subtotal resection was performed seemed to have improved DFS rate at three years compared to those who underwent more extensive surgery (58% vs. 49%, p ¼ 0.07; results not shown). This reflects more favorable disease profile in distal subtotal resection subgroup, i.e. the size and the location (gastric antrum) of the tumor which allowed less extensive surgery. In addition, patients with pretreatment Hb concentration 110 g/l had worse prognosis than those with higher Hb values. Negative prognostic impact of low Hb concentration may result from a possible relationship with hypoxia in surgically perturbed tissues, which reduces the sensitivity of tumor cells to both, RT as well as ChT.33,34 However, it is more likely that the low Hb level is a marker for extensive disease, poor nutrition and depressed immunity, reflected in poor performance status of the patients. Surprisingly, the patients who were administered a total dose of more than 4000 mg 5-FU per five-day cycle had worse survival than those whose total dose was 4000 mg or less. It might be the case, that this observation reflects the delicateness in the balance between the efficacy and toxicity. As the number of patients receiving more than 4000 mg 5-FU per five-day cycle was low (14 patients only), no firm conclusion could be made. Conclusions Even though the present study is a retrospective analysis of a single institution, it may represent a solid ground for some relevant conclusions to be drawn. As no answer can be given regarding the effectiveness of the applied treatment regimen, we can certainly suggest that in operable gastric carcinoma, postoperative adjuvant radiochemotherapy is feasible and its toxicity acceptable. In our cohort of patients, lower pT-stage (pT1e2), less extensive involvement of the stomach with the cancer, pretreatment Hb concentration 110 g/l, and <4000 mg of 5-FU per five-day cycle were recognized as independent favorable prognostic factors. For reliable estimation of the survival benefit of postoperative chemoradiation in operable gastric adenocarcinoma,

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a prospective randomized trial comparing surgery only and postoperative chemoradiation is required. Furthermore, additional benefit could be expected from introducing intensity modulated radiotherapy (IMRT),35 whereas the next logical step in evaluation of adjuvant treatment in this poor prognosis disease is the comparison with neoadjuvant radiochemotherapy.36 References 1. Cancer incidence in Slovenia 2002. Cancer Registry of Slovenia. Ljubljana: Institute of Oncology; 2005. 2. Smalley SR, Gunderson L, Tepper J, et al. Gastric surgical adjuvant radiotherapy consensus report: rationale and treatment implementation. Int J Radiat Oncol Biol Phys 2002;52:283–93. 3. Kocakova I, Vetcha H, Soumarova R, Vyzula R. Role of adjuvant chemoradiotherapy in the treatment of gastric carcinoma. Cas Lek Cesk 2003;142:26–8. 4. Gunderson LL, Burch PA, Donohue JH. The role of irradiation as a component of combined modality treatment for gastric carcinoma. J Infus Chemother 1995;5:117–24. 5. Gunderson LL, Sosin H. Adenocarcinoma of the stomach: areas of failure in a reoperation series (second or symptomatic look) clinicopathological correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1982;8:1–11. 6. Hartgrink HH, van de Velde CJ, Putter H, et al. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomised Dutch Gastric Cancer Group Trial. J Clin Oncol 2004; 22:2067–77. 7. Noguchi Y, Yoshikawa T, Tsuburaya A, Motohashi H, Karpeh MS, Brennan MF. Is gastric carcinoma different between Japan and the United States? Cancer 2000;89:2237–46. 8. Smalley SR, Gunderson LL. Stomach. In: Perez CA, Brady LW, editors. Principles and practice of radiation oncology. 3rd ed. Philadelphia: Lippincott-Raven Publishers; 1997, p. 1149–460. 9. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–30. 10. Moertel CG, Childs DS, O’Fallon JR, Holbrook MA, Schutt AJ, Reitmeir RJ. Combined 5-fluorouracil and radiation therapy as a surgical adjuvant for poor prognosis gastric carcinoma. J Clin Oncol 1984; 2:1249–54. 11. Bora H, Unsal D, Akmansu M. Results of chemoirradiation after curative resection of locally advanced gastric cancer. Int J Clin Pract 2004;58:451–6. 12. Jansen EP, Boot H, Cats A, van Coevorden F, Zoetmulder FA, Verheij M. New insights in the adjuvant treatment of gastric cancer. Ned Tijdschr Geneeskd 2004;148:2529–34. 13. Schendera A, Seegenschmiedt MH. Adjuvant therapy concepts in advanced stomach carcinoma. Future treatment not without irradiation? MMW Fortschr Med 2003;145:36–8. 14. Dahan L, Atlan D, Bouche O, et al. Postoperative chemoraditherapy after surgical resection of gastric adenocarcinoma: can LV5FU2 reduce the toxic effects of the MacDonald regimen? A report on 23 patients. Gastroenterol Clin Biol 2005;29:7–10. 15. Sobin LH, Wittekind CH. International Union Against Cancer (UICC): TNM classification of malignant tumours. 6th ed. New York: Wiley-Liss; 2002. 16. World Health Organisation. WHO handbook for reporting results of cancer treatment. Geneva: WHO; 1997.

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