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Oesophagogastric cancer: exploring the way to an individual approach
Stiekema, J.
Publication date
2015
Document Version
Final published version
Link to publication
Citation for published version (APA):
Stiekema, J. (2015). Oesophagogastric cancer: exploring the way to an individual approach.
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EDWIN P.M. JANSEN HENK BOOT
ANNEMIEKE CATS OLGA BALAGUE PONZ MARCEL VERHEIJ
JOHANNA W. VAN SANDICK * CONTRIBUTED EQUALLY
THE PROGNOSTIC SIGNIFICANCE OF
AN R1 RESECTION IN GASTRIC CANCER
PATIENTS TREATED WITH ADJUVANT
CHEMORADIOTHERAPY
ABSTRACT Background
A microscopically irradical (R1) resection is a well known adverse prognostic factor after gastric cancer surgery. However, the prognostic significance of an R1 resection in gastric cancer patients who are treated with chemoradiotherapy (CRT) following the operation has poorly been studied. Therefore, the aim of this study was to evaluate the impact of an R1 resection on (recurrence free) survival in gastric cancer patients who were treated with CRT after surgery.
Methods
Gastric cancer patients who had undergone a resection with curative intent followed by adjuvant CRT at our institute between 2001 and 2011 were included. CRT consisted of radiotherapy (45 Gy/25 fractions) combined with concurrent capecitabine (with or without cisplatin) or 5-fluorouracil/leucovorin.
Results
A consecutive series of 110 patients was studied, including 80 (73%) patients who had undergone an R0 resection and 30 (27%) patients with an R1 resection. Pathological T-classification (p = 0.26), N-classification (p = 0.77) and histological subtype according to Laurén (p = 0.071) were not significantly different between these groups. Three-year recurrence free survival (45% versus 35%, p = 0.34) and overall survival (47% versus 48%, p = 0.58) did not significantly differ between patients who had undergone an R0 or R1 resection. In a multivariate analysis, pathological T-classification and N-classification were independent prognostic factors for survival.
Conclusion
A microscopically irradical (R1) resection was not an adverse prognostic factor in gastric cancer patients who had undergone chemoradiotherapy after the operation.
THE PROGNOSTIC SIGNIFICANCE OF AN R1 RESECTION IN GASTRIC CANCER PATIENTS
INTRODUCTION
In Western countries, most patients with gastric cancer present with advanced disease and have a dismal overall survival.1 Complete surgical resection remains the cornerstone
of potentially curative treatment. However, even after a microscopically radical (R0) surgical resection, the disease will recur in a majority of patients.2-3 In the past decade,
neoadjuvant and adjuvant treatment strategies have improved overall survival, and have therefore become standard of care. A well appreciated multimodality approach is adjuvant chemoradiotherapy (CRT).4 In a recent update of the INT-0116 study, the benefit
of adjuvant CRT after a radical (R0) resection for gastric cancer was confirmed.5 The lower
rate of locoregional recurrence in the adjuvant CRT group compared to the surgery only group (24% versus 47%) suggests that the survival benefit of CRT is mainly caused by increased locoregional control. As yet, adjuvant CRT in gastric cancer treatment has been investigated almost invariably in patients who had undergone an R0 resection.4, 6-7 A tumour positive resection margin, defined as an R1 resection, occurs in 2 – 22% of
patients and has often been documented as a poor prognostic factor.8 A re-resection to
obtain tumour negative margins has been advocated.9 However, clear guidelines after an
R1 resection are lacking and the value of surgical re-intervention is still under debate.10-11
As adjuvant CRT increases locoregional control after gastric cancer surgery, patients with an R1 resection may benefit from such intensified local treatment. However, adjuvant CRT after an R1 resection in gastric cancer patients has been poorly studied. In this retrospective study, we evaluated the impact of an R1 resection on (recurrence free) survival in gastric cancer patients who were treated with CRT after surgery.
METHODS Patients
In 2001, an adjuvant CRT program to optimize outcome of gastric cancer surgery was started in our institute. Our institute is a tertiary referral center for gastric cancer treatment and has long been the only institute where adjuvant CRT was administered. Gastric cancer patients who had undergone adjuvant chemoradiotherapy at our institute between 2001 and 2011 were included. The operation had been performed at our institute or in an other hospital in the Netherlands. Only patients who had undergone a resection with curative intent were included. A potentially curative resection was defined as a macroscopically complete resection with no evidence of peritoneal or distant metastases.
Histopathology
All surgical resection specimens from patients referred for adjuvant chemoradiotherapy were re-evaluated at our institute. For the current analysis, staging of disease was done according to the pathological (pTNM) classification of the American Joint Committee on Cancer (AJCC), 7th edition.12 Histological subtype according to Laurén’s classification was
was defined as the presence of tumour cells in the proximal and/or distal resection margin on staining with haematoxylin & eosin (H&E). In doubtful cases, at the discretion of the pathologist, stains were performed with CAM 5.2 or pankeratine.
Surgery and adjuvant chemoradiotherapy
According to the national guidelines, gastric cancer resection was preferably combined with at least a D1 lymph node dissection without routine splenectomy or pancreatic tail resection. If a macroscopic margin of 6 cm between the tumour and the resection line could not be obtained, intra-operative frozen margins were performed when a more extensive resection was considered feasible. From January 2001 until December 2002 patients were treated with adjuvant CRT according to the Intergroup 0116 trial.4 Between
December 2002 and July 2008, patients were treated with adjuvant CRT within phase I/II clinical trials.14-16 In these trials, patients with adenocarcinoma of the stomach or
oesophagogastric junction in AJCC Stage Ib – IV (M0) were included. Patients could be treated in these studies after an R0 or R1 resection and if their caloric intake, renal and liver function allowed chemoradiation. Thereafter, this adjuvant treatment has been advised routinely for patients who had not been treated with preoperative therapy and for those who are at increased risk for locoregional tumour recurrence, i.e. in case of an R1 resection and/or extensive lymph node involvement. The total radiation dose of 45 Gy given in 25 fractions of 1.8 Gy in 5 weeks was similar in all schedules, while (concurrent) chemotherapy regimens differed. The Intergroup 0116 trial schedule contained 5-fluorouracil (5-FU) and leucovorin (LV) on the first 4 and last 3 days of radiotherapy (RT). Patients also received one cycle of 5-FU and LV during 5 days before CRT and two cycles thereafter. The phase I/II study schedules contained 2 weeks capecitabine monotherapy prior to the CRT followed by concurrent capecitabine with or without cisplatin (escalating doses of 3-6 mg/m2 i.v. daily on all RT days or 20-25 mg/m2 i.v. weekly on RT days 1, 8, 15,
22 and 29). The clinical target volume encompassed the preoperative tumour extension, gastric bed, gastric remnant when present, anastomosis and surrounding lymph node basins/stations.16
Follow-up
Follow-up visits were performed every 3 months during the first two years and every 6 months thereafter. CT-scans of the abdomen were performed on indication or according to the involved study protocol. Follow-up data were collected until death or September 2012. Definition of tumour recurrences
Data on the first localization of tumour recurrence was collected. Tumour recurrences were categorized as locoregional recurrence, peritoneal carcinomatosis or distant metastasis. Locoregional recurrence included tumour recurrence in the gastric bed, at the anastomotic site, duodenal stump or locoregional lymph node stations. Peritoneal recurrence was defined as malignant ascites with or without peritoneal deposits on CT-scan. Distant metastasis was defined as tumour recurrence in other organs or distant lymph nodes.
THE PROGNOSTIC SIGNIFICANCE OF AN R1 RESECTION IN GASTRIC CANCER PATIENTS
Statistics
Patient characteristics were compared using the X2-test or Fisher’s exact test where
appropriate. Recurrence free survival (RFS) was defined as the period between surgery and the date of the first documented disease recurrence at any site. Overall survival (OS) was calculated from date of surgery until death from any cause. Survival was estimated using the Kaplan-Meier method and compared with the log-rank test. A Cox proportional hazards model was used to perform uni- and multivariate analyses of prognostic factors for RFS. All tests were two-sided and a P value < 0.05 was considered significant. SPSS statistical software (SPSS, Chicago,IL, version 20.0) was used for analysis.
Figure 1. Gastric cancer patients who had undergone adjuvant chemoradiotherapy after a resection with curative intent between January 2001 and December 2011
RESULTS Patients
Between 2001 and 2011, 170 consecutive patients were treated with adjuvant chemoradiotherapy at our institute after a potentially curative resection for gastric cancer (Figure 1). Patients who received preoperative therapy (N = 41) and patients who had an oesophagogastric junction tumour (N = 19) were excluded, leaving 110 patients who were included in this study. Median follow-up for the entire study population was 28 months (range 5 – 115 months) and for surviving patients 76 months (range 9 - 115 months). No patients were lost to follow-up.
Clinicopathological characteristics
Clinical and pathological characteristics are summarized in Table 1. There were 80 patients (73%) who had undergone an R0 resection and 30 patients (27%) who had undergone an R1 resection. In R1 resected patients, the duodenal margin was involved in 12 patients (40%), the proximal margin in 12 patients (40%) and both margins in 6 patients (20%). Seven of 12 patients with an involved proximal margin had undergone a total gastrectomy. Patients with an R1 resection were more often female (P = 0.019). There were no other statistically significant differences between the R0 and R1 groups. Median follow-up was 28 months (5 – 115 months) for patients who underwent an R0 resection and 24 months (6 – 105 months) for those who underwent an R1 resection (P = 0.584).
Recurrence free and overall survival
In the total study population, 69 patients developed disease recurrence. The 3- and 5-year RFS for all patients were 43% and 33%, respectively. In the group of patients who developed disease recurrence, the first site of tumour recurrence was noted with similar frequencies for a locoregional recurrence, peritoneal or distant metastasis (Figure 2a). Median time to locoregional, peritoneal and distant tumour recurrence was 16, 9 and 12 months respectively (P = 0.103). In the R0 group, 48 patients (60%) developed disease recurrence compared to 21 patients (70%) in the R1 group (Figure 2b and c). Localization of the first tumour recurrence did not differ between groups (P = 0.747, Figure 2b and c). Two of 30 (7%) patients with an R1 resection developed recurrence at the R1 site. In both patients this was a recurrence at the anastomotic site. The 3- and 5-year RFS rates for patients with an R0 resection were 45% and 35%, respectively, compared to 38% and 28% for patients with an R1 resection (P = 0.343, Figure 3a). Also, overall survival was not significantly different between R0 and R1 resected patients (P = 0.581, Figure 3b). Prognostic factors for recurrence free survival
In a univariate Cox regression analysis, tumour location, extent of gastric resection, pathological T-classification and pathological N-classification were significant prognostic factors for RFS (Table 2). In a multivariate analysis, pathological T-classification (P < 0.001) and N-classification (P < 0.001) were independent significant prognostic factors
THE PROGNOSTIC SIGNIFICANCE OF AN R1 RESECTION IN GASTRIC CANCER PATIENTS
Table 1. Clinicopathological characteristics of gastric cancer patients treated with adjuvant chemoradiotherapy according to radicality of the resection
R0, microscopically radical resection; R1, microscopically irradical resection; 5-FU, 5-Fluorouracil; LV, Leucovorin #Pearson X2-test
†Fisher’s exact test
* According to Laurén’s classification13
** According to the pathological (pTNM) classification of the American Joint Committee on Cancer 7th edition12
Table 1. Clinicopathological characteristics of gastric cancer patients treated with adjuvant chemoradiotherapy according to radicality of the resection.
R0, microscopically radical resection; R1, microscopically irradical resection; 5-FU, 5-Fluorouracil; LV, Leucovorin
#Pearson X2-test †Fisher’s exact test
* According to Laurén’s classification13
** According to the pathological (pTNM) classification of the American Joint Committee on Cancer 7th
edition12
Characteristics All patients N (%) R0 resection N (%) R1 resection N (%) valueP- #
All patients 110 (100) 80 (73) 30 (27) Sex - Male - Female 77 (70) 33 (30) 61 (76) 19 (24) 16 (53) 14 (47) 0.019# Age in years - ≤ 60 - > 60 64 (58) 46 (42) 45 (56) 35 (44) 19 (63) 11 (37) 0.502 # Tumour location - Proximal - Middle - Distal - Overlapping 13 (12) 26 (24) 62 (56) 9 (8) 9 (11) 21 (26) 45 (56) 5 (6) 4 (13) 5 (17) 17 (57) 4 (13) 0.519#
Extent of gastric resection - Partial gastrectomy
- Total gastrectomy 70 (64) 40 (36) 51 (64) 29 (36) 19 (63) 11 (37) 0.968
#
Number of evaluated lymph nodes
- < 15 - ≥ 15 68 (62) 42 (38) 47 (59) 33 (41) 21 (70) 9 (30) 0.379 † Histological subtype * - Intestinal type - Diffuse type 38 (35) 72 (65) 32 (40) 48 (60) 6 (20) 24 (80) 0.071 † pT classification ** - T1 - T2 - T3 -T4a - T4b 3 (3) 6 (5) 50 (46) 45 (41) 6 (5) 3 (4) 6 (7) 38 (48) 29 (36) 4 (5) 0 (0) 0 (0) 12 (40) 16 (53) 2 (7) 0.257# pN classification** - N0 - N1 - N2 - N3 13 (12) 17 (15) 38 (35) 42 (38) 8 (10) 12 (15) 29 (36) 31 (39) 5 (17) 5 (17) 9 (30) 11 (36) 0.770# Chemoradiotherapy regimen - 5-FU/LV + 45 Gy - Capecitabine + 45 Gy - Capecitabine/cisplatin + 45 Gy 5 (4) 47 (43) 58 (53) 4 (5) 34 (43) 42 (52) 1 (4) 13 (43) 16 (53) 0.933#
for recurrence free survival. Radicality of the resection was not a prognostic factor (multivariate Cox HRR1 vs. R0 0.93, 95% CI 0.53 – 1.63, P = 0.792).
b. After an R0 gastric cancer resection and adjuvant chemoradiotherapy (N = 48)
c. After an R1 gastric cancer resection and adjuvant chemoradiotherapy (N = 21) Figure 2a - c. Site of first tumour recurrence in all patients who developed disease recurrence
a. After gastric cancer resection and adjuvant chemoradiotherapy (N = 69)
DISCUSSION
After publication of the INT-0116 study, adjuvant chemoradiotherapy has been established as one of the treatment modalities that improves survival after a microscopically radical resection for gastric cancer.4 The recently updated analysis of this trial showed
a continuous benefit of adjuvant CRT at 10 years follow-up.5 The median RFS in the
adjuvant CRT arm (27 months), as well as the 3-year RFS (48%) and OS (50%) are in line with the results from the current series (median RFS 26 months, 3-year RFS 45% and OS 48%). RFS and OS rates from the MAGIC study, in which patients were randomized between surgery only and perioperative chemotherapy, are also comparable to the current study.17 Obviously, comparing outcomes between different studies has its
THE PROGNOSTIC SIGNIFICANCE OF AN R1 RESECTION IN GASTRIC CANCER PATIENTS
Figure 3a. Recurrence free survival for all patients treated with adjuvant chemoradiotherapy after gastric cancer resection (N = 110) according to radicality of the resection
Figure 3b. Overall survival for all patients treated with adjuvant chemoradiotherapy after gastric cancer resection (N = 110) according to radicality of the resection
limitations, but we believe that the survival results in the current study are representative for a Western patient series. One major difference with the INT-0116 study is the inclusion of 30 patients (27%) who underwent an R1 resection, an adverse prognostic factor in many studies.9, 18-20 With the exception of gender, there were no significant differences in
clinical, surgical and pathological factors between patients who had undergone an R0 or R1 resection.
Table 2: Cox regression model of prognostic factors for recurrence free survival.
3-year RFS Univariate Multivariate HR (95% CI) P HR (95% CI) P Sex - Male - Female 44 % 41 % Ref. 0.82 (0.50 – 1.37) 0.454 Age in years - ≤ 60 - > 60 42 % 44 % 1.04 (0.64 – 1.68) Ref. 0.888 Tumour location - Proximal - Middle - Distal - Overlapping 15 % 42 % 54 % 13 % Ref. 0.39 (0.19 – 0.81) 0.28 (0.15 – 0.54) 0.85 (0.35 – 2.06) 0.047 # 0.011 < 0.001 0.721 Ref. 0.44 (0.20 – 0.95) 0.26 (0.12 – 0.57) 0.84 (0.33 – 2.15) 0.121# 0.035 0.001 0.720 Extent of gastric resection
- Partial gastrectomy
- Total gastrectomy 52 % 27 % 1.97 (1.22 – 3.17) Ref. 0.005 1.35 (0.75 – 2.41) Ref. 0.318
Number of evaluated lymph nodes - < 15 - ≥ 15 44 % 43 % Ref. 1.35 (0.84 – 2.18) 0.217 Radicality of resection - R0 - R1 45 % 38 % Ref. 1.28 (0.77 – 2.14) 0.345 Ref. 0.93 (0.53 – 1.63) 0.792 Histological subtype* - Intestinal type
- Diffuse type 45 % 42 % 1.16 (0.70 – 1.92) Ref. 0.572
pT classification† **
- T1 - 3
-T4a/b 58 %26 % 2.49 (1.54 – 4.04)Ref. < 0.001 3.20 (1.84 – 5.56)Ref. < 0.001
pN classification** - N0-1 - N2 - N3 73 % 40 % 27 % Ref. 2.48 (1.16 – 5.32) 4.68 (2.24 – 9.78) < 0.001# 0.019 < 0.001 Ref. 2.71 (1.20 – 6.16) 4.89 (2.28 – 10.47) < 0.001# 0.017 < 0.001 RFS, Recurrence free survival; HR, Hazard Ratio; CI, Confidence Interval; R0, microscopically radical
resection; R1, microscopically irradical resection
# Test of trend
* According to Laurén’s classification13
** According to the pathological (pTNM) classification of the American Joint Committee on Cancer 7th
edition12
† Because of the limited number of patients in subgroups, patients were grouped according to the absence
(pT1-3) or presence (pT4a/b) of serosal invasion
Table 2. Cox regression model of prognostic factors for recurrence free survival
RFS, Recurrence free survival; HR, Hazard Ratio; CI, Confidence Interval; R0, microscopically radical resection; R1, microscopically irradical resection
# Test of trend
* According to Laurén’s classification13
** According to the pathological (pTNM) classification of the American Joint Committee on Cancer 7th edition12
† Because of the limited number of patients in subgroups, patients were grouped according to the absence (pT1-3) or presence (pT4a/b) of serosal invasion
THE PROGNOSTIC SIGNIFICANCE OF AN R1 RESECTION IN GASTRIC CANCER PATIENTS
In the current study, 3- and 5-year RFS and OS were not significantly different between patients with an R0 or R1 resection. In a Cox regression analysis, radicality of the resection was not a prognostic factor for recurrence free survival. These results are in contrast to several other studies on adjuvant CRT after an R0 or R1 resection for gastric cancer.21-26 Most of these studies are small and/or included a limited number of patients
with an R1 resection.21-25 An exception is a recently published Israeli study, in which 37
of 166 (22%) patients who had undergone surgical resection followed by adjuvant CRT had an R1 resection.26 These patients had a significantly worse survival compared to
patients with an R0 resection (3-year RFS 29% versus 60%). However, since the primary aim of that study was to assess the feasibility of the INT-0116 regime, clinicopathological characteristics were not given per group and no multivariate analysis to correct for possible confounders (e.g. more advanced T- and N-stage) was performed. Therefore, the results regarding the impact of an R1 resection on outcome need to be interpreted with caution.
When tumour positive resection margins are found on frozen section examination during surgery and a tumour negative resection margin can be easily obtained, extended surgery is a clear option.27 A clinical dilemma arises when a tumour negative
margin can only be obtained by extending the operation to a distal oesophagectomy or pancreaticoduodenectomy which carries substantially increased morbidity.28 When
tumour positive margins are found after surgery, the team is confronted with the difficult question whether to perform a re-resection (if possible). Opinions in current literature vary from watchful waiting,10 to re-resection in patients with limited nodal disease19 or
re-resection whenever feasible.9, 20 The possible benefit of performing a re-resection is
mainly based on the prognostic impact of tumour positive margins, with the rationale that obtaining tumour negative margins can negate this adverse prognostic effect. The results from the current study suggest that tumour positive margins have no prognostic impact in gastric cancer patients treated with adjuvant CRT. These results challenge the benefit of performing a re-resection in these patients. Currently, formal studies on how to manage gastric cancer patients after an R1 resection are scarce. In one recent retrospective study by Chen et al., survival of patients who had undergone a re-resection after tumour positive margins were found was improved compared to patients who did not undergo a re-resection (median overall survival 23 months versus 18 months, P = 0.019).29 To our knowledge, the effect of adjuvant CRT after an R1 resection has only
been investigated in one previous study, also by our group.30 In this study, adjuvant CRT
was associated with an OS benefit compared to surgery alone in R1 resected gastric cancer patients. Adjuvant CRT (45 Gy with weekly cisplatin and daily capecitabine) has acceptable hematological and gastro-intestinal toxicity (around 32% grade III and 3% grade IV according to NCI Common Toxicity Criteria 3.0).14, 16
There are several limitations to the current study mainly associated with its retrospective design. The inclusion of a selected group of patients, i.e. those with an increased risk for locoregional tumour recurrence might have introduced bias. This is the reason for the
large proportion of R1 resected patients (27%) in the current study. Also, as is frequently seen in Western patient series, the current study is limited by a low lymph node yield (< 15 lymph nodes) in a majority of patients. This could have lead to an inaccurate N-classification. Obviously, the role of adjuvant CRT in gastric cancer patients who have undergone an R1 resection would best be studied in a phase III randomized trial. It is unlikely that such a trial will be performed. In the CRITICS study (NCT00407186), patients with resectable gastric cancer are randomised before the start of neoadjuvant chemotherapy between adjuvant chemotherapy and adjuvant chemoradiotherapy.31 All patients undergo at least D1+ surgery with at least 15 lymph nodes. In patients with an R1 resection, adjuvant treatment is given according to randomization. A subgroup analysis in the CRITICS study might shed further light on the optimal adjuvant treatment strategy for patients who have undergone an R1 gastric cancer resection. Finally, we wish to emphasize that the current study does not undermine the value of meticulous surgery in the outcome of gastric cancer treatment.
In conclusion, a microscopically irradical (R1) resection was not associated with a higher tumour recurrence rate, nor did it lead to poorer overall survival in a consecutive series of gastric cancer patients treated with adjuvant CRT after the operation.
THE PROGNOSTIC SIGNIFICANCE OF AN R1 RESECTION IN GASTRIC CANCER PATIENTS
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