Ann Surg Oncol DOI 10.1245/s10434-016-5306-0
ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
CRS-HIPEC Prolongs Survival but is Not Curative for Patients with Peritoneal Carcinomatosis of Gastric Cancer T. Boerner1, A. Graichen1, T. Jeiter1, F. Zemann2, P. Renner1, L. Ma¨rz3, Y. Soeder1, H. J. Schlitt1, P. Piso3, and M. H. Dahlke1 Department of Surgery, University Medical Center Regensburg, Regensburg, Germany; 2Center for Clinical Studies, University Medical Center Regensburg, Regensburg, Germany; 3Department of Surgery, St. John of God Hospital Regensburg, Regensburg, Germany
1
ABSTRACT Purpose. Peritoneal carcinomatosis (PC) is a dismal feature of gastric cancer that most often is treated by systemic palliative chemotherapy. In this retrospective matched pairs-analysis, we sought to establish whether specific patient subgroups alternatively should be offered a multimodal therapy concept, including cytoreductive surgery (CRS) and intraoperative hyperthermic chemotherapy (HIPEC). Methods. Clinical outcomes of 38 consecutive patients treated with gastrectomy, CRS and HIPEC for advanced gastric cancer with PC were compared to patients treated by palliative management (with and without gastrectomy) and to patients with advanced gastric cancer with no evidence of PC. Kaplan–Meier survival curves and multivariate Cox regression models were applied. Results. Median survival time after gastrectomy was similar between patients receiving CRS-HIPEC and matched control patients operated for advanced gastric cancer without PC [18.1 months, confidence interval (CI) 10.1– 26.0 vs. 21.8 months, CI 8.0–35.5 months], resulting in comparable 5-year survival (11.9 vs. 12.1 %). The median survival time after first diagnosis of PC for gastric cancer was 17.2 months (CI 10.1–24.2 months) in the CRSHIPEC group compared with 11.0 months (CI 7.4– 14.6 months) for those treated by gastrectomy and chemotherapy alone, resulting in a twofold increase of 2-year survival (35.8 vs. 16.9 %).
Ó Society of Surgical Oncology 2016 First Received: 24 February 2016 M. H. Dahlke e-mail:
[email protected]
Conclusions. We provide retrospective evidence that multimodal treatment with gastrectomy, CRS, and HIPEC is associated with improved survival for patients with PC of advanced gastric cancer compared with gastrectomy and palliative chemotherapy alone. We also show that patients treated with CRS-HIPEC have comparable survival to matched control patients without PC. However, regardless of treatment scheme, all patients subsequently recur and die of disease.
Gastric cancer most often is managed by surgery and/or chemotherapy. The clinical options for the management of early gastric cancer are unambiguous with complete surgical resection as the mainstay of therapy. The management of choice for the treatment of locally advanced gastric cancer, perioperative chemotherapy followed by gastrectomy, and D2 lymphadenectomy is based on solid clinical evidence.1–4 The diagnosis of peritoneal carcinomatosis (PC) in addition to any stage of gastric cancer traditionally has been considered a cutoff point for surgical intervention. In such cases, palliative chemotherapy is the preferred treatment option for patients with PC. Some have advocated staging laparoscopy at the time of gastric cancer diagnosis to exclude patients with PC from gastrectomy.5 These dichotomic treatment pathways for patients with and without PC cause a situation in which locally advanced gastric cancers, some of them with many positive lymph nodes, generally are subjected to aggressive multimodality treatment with neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy, whereas less advanced tumors with PC are usually managed with palliative chemotherapy only. It remains an open question if this strict biological classification of advanced gastric cancer with and without
T. Boerner et al.
PC is legitimate from a clinical standpoint or whether PC should not be considered an equal prognostic feature to a high rate of positive lymph nodes. Without question, PC from gastric cancer is a dismal facet of the disease and the outlook for long-term survival after the histological diagnosis is poor. Even the presence of positive cytology from peritoneal washings after staging laparoscopy at the time of diagnosis is associated with essentially no long-term survival.6 However, a comparable natural course of the disease often can be observed with advanced lymphatic spread. The obvious practical difference between both characteristics of the disease is that PC can be diagnosed early and lymphatic spread is usually a postoperative pathological diagnosis. This merely practical distinction has shaped the current strategies for the treatment of advanced gastric cancer; yet is this truly justified when comparing the biology of gastric cancer PC with other negative predictors of survival from gastric cancer? In this current retrospective work, we ask whether developments in aggressive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) that now enable treatment of PC (in particular when the PC burden is low, PCI \10) analogous to that of lymphatic metastases should consequently challenge perceptions of the relevance of PC in gastric cancer. PATIENTS AND METHODS Between January 2006 and January 2013, 55 consecutive patients with PC of advanced gastric cancer were treated with HIPEC at the University Medical Center Regensburg or the St. John of God Hospital Regensburg (CRS-HIPEC group). Both institutions have a special focus on the procedure with [50 interventions per year. HIPEC was performed with the ‘‘closed abdomen’’ technique with a targeted intraperitoneal temperature of 42–43 °C. All HIPEC patients received 75 mg/m2 of cisplatin combined with 15 mg/m2 of doxorubicin for 60 min. Eight patients were excluded due to distant metastases or additional malignant disease and a further nine due to insufficient follow-up or when no gastrectomy was performed. For comparison of clinical outcome, the resulting 38 HIPEC patients were retrospectively matched with respect to pathological tumor-node-metastasis (TNM) stage to patients with PC of advanced gastric cancer, which received standard treatment with systemic chemotherapy
and no CRS/HIPEC (PC-standard group) and to patients with advanced gastric cancer without evidence of PC (NoPC group). The order of matching began with T stage, then N stage, and then the closest age match to find control cohorts with suspected equal biological behavior. For TNM matching, PC was not considered metastatic disease. The matching was supervised by the biostatistician (FZ). All patients in the matched groups were treated by gastrectomy during their clinical course. Only PC patients with a peritoneal cancer index PCI \10, in whom complete cytoreduction (CCR-0) could be achieved, were subjected to CRS and HIPEC. Patients with advanced gastric cancer that received standard treatment only without gastrectomy were summarized as an additional palliative group. For an overview about the groups see Table 1. Data analysis was performed using the SPSS statistical program (Statistical Package for Social Science, version 20.0). Proportions of variables were compared using the unpaired t test and the v2 test, unless expected cell counts were \5 in which case Fisher’s exact test was used. Survival rates were calculated by using the Kaplan–Meier method and results were validated by using the log-rank test. Cox regression analysis was used to identify independent factors significantly associated with overall survival (OS). A p value \0.05 was considered to be statistically significant. The statistical work was overseen by a biostatistician (FZ). The study was approved by the institutional review board of Regensburg University Medical Center. RESULTS Demographics and Clinical Characteristics A total of 103 patients with advanced gastric cancer were chosen for this matched-pairs analysis (Table 1). Of all patients in the observation period, 65 patients with gastric cancer developed PC without distant metastatic disease in their clinical course. Of these, 38 patients (58.5 %) were treated by CRS and HIPEC (CRS-HIPEC group), whereas 27 patients (41.5 %) did not receive HIPEC and were treated by standard therapy predominantly based on chemotherapy (PC-standard group). The selection for or against CRS and HIPEC was not only based on fitness for surgery but was significantly influenced by the patients’ choice. Thirty-eight patients with advanced
TABLE 1 Overview of groups and patient characteristics CRS-HIPEC group
PC-standard group
No-PC group
Palliative group
Surgery
Gastrectomy
Gastrectomy
Gastrectomy
No gastrectomy
PC
PC present (PCI \10)
PC present (PCI \10)
No PC
PC present
Chemotherapy
CRS-HIPEC
Chemotherapy only
Stage adjusted
Palliative treatment
CRS-HIPEC Prolongs Survival but is Not Curative for Patients
1,0
CRS-HIPEC PC-Standard CRS+HIPEC-censored PC-Standard-censored
0,8
Survival
gastric cancer without evidence of PC were matched to the CRS-HIPEC patients. These patients received a gastrectomy (No-PC group) with lymphadenectomy. Regarding tumor stage, pathological tumor-node-status, sex, and grading there were no significant differences between the CRS-HIPEC group and the other groups. However, the mean age at surgery was significant lower in the CRSHIPEC group compared with the No-PC group (52.6 vs. 60.6 years; p = 0.004). When assessing the primary gastric tumor on routine pathology, no evidence of residual (local) tumor could be achieved in 24 patients (63.2 %) of the CRS-HIPEC group, which was not different to the PCstandard group (74.1 %). In comparison, a significantly higher rate of R0 resection (94.7 %; p = 0.001) was achieved in patients without PC. Apart from one patient, all patients in the CRS-HIPEC group (94.7 %) were subjected to additional systemic chemotherapy; most of them used a preoperative approach (92.1 %). Patients with PC did not receive HIPEC were treated by systemic chemotherapy as often as HIPEC patients altogether but had a significantly lower rate of preoperative versus postoperative setups (48.1 vs. 92.1 %; and 70.4 vs. 23.7 % respectively; p \ 0.001 for both). Patients without evidence of PC, on the other hand, were treated by systemic chemotherapy in half of the cases only (50.0 %; p \ 0.001). Some of these patients had T2 tumors, and some were treated in an era in which neoadjuvant chemotherapy was not yet thoroughly established.
0,6
p=0.004 0,4
0,2
0,0 ,0
20,0
60,0
40,0
Time after first diagnosis of PC (months) 1-yearsurvival
2-yearssurvival
3-yearssurvival
5-yearssurvival
CRS-HIPEC (n=38)71.1%
35.8%
24.1%
6.4%
PC-Standard (n=27)33.3%
16.9%
0%
0%
FIG. 1 a Kaplan–Meier analysis of matched pairs with PC treated with CRS-HIPEC or standard therapy only. There was a significantly better OS after first diagnosis of PC in patients receiving CRS with intraoperative HIPEC. b Survival rates after first diagnosis of PC of matched pairs with PC treated with CRS-HIPEC or standard therapy only
1,0
CRS-HIPEC Palliative CRS+HIPEC-censored Palliative-censored
Survival 0,8
Survival
The median survival time after first diagnosis of PC for gastric cancer was 17.2 months [95 % confidence interval CI 10.1–24.2 months] in the selected patient population that received CRS-HIPEC, including gastrectomy (CRSHIPEC group), compared with 11.0 months (95 % CI 7.4– 14.6 months) for those who had gastrectomy and no HIPEC (PC-Standard group). Only about 30 % of patients with PC who did not receive HIPEC survived the first year after diagnosis of PC, and no patient was alive after 3 years. In contrast, more than 70 % of patients in the CRS-HIPEC group were alive at 1 year, and 5 of 65 patients survived more than 3 years (Fig. 1). This accounts for a significant difference in overall survival after first diagnosis of PC between both groups (p = 0.004) in this retrospective matched-pairs analysis (compare matching strategy above). However, no long-term survival was detected in both groups irrespective of intraperitoneal therapy (Fig. 1). In palliative patients, who received no surgical therapy (no gastrectomy, no HIPEC), the outcome was even worse as expected (Fig. 2). The median survival in this group was 7.7 months with 97 % mortality in the first 2 years after first diagnosis of PC (Fig. 2).
0,6
p<0.001 0,4
0,2
0,0 20
0
40
60
Time after first diagnosis of PC (months) 1-yearsurvival
2-yearssurvival
3-yearssurvival
5-yearssurvival
CRS-HIPEC (n=38) 71.1%
35.8%
24.1%
6.4%
Palliative (n=31)
3.2%
0%
0%
29.0%
FIG. 2 a Kaplan–Meier analysis of patients with advanced gastric cancer with PC treated with CRS-HIPEC versus palliative patients. b Survival rates after first diagnosis of PC of patients with advanced gastric cancer with PC treated with CRS-HIPEC versus palliative patients
T. Boerner et al. TABLE 2 Univariate and multivariate analysis of prognostic factors for overall survival in patients with advanced gastric cancer receiving HIPEC or standard therapy only Univariate analysis
Multivariate analysis
p value
HR
95 % CI
p value
HR
95 % CI
HIPEC
0.005
0.454
(0.262–0.785)
0.008
0.477
(0.275–0.828)
Age [ 56 years
0.040
1.784
(1.026–3.100)
0.050
1.753
(1.000–3.073)
N0 T1/T2
0.061 0.491
0.484 1.233
(0.226–1.034) (0.679–2.237)
0.070
0.492
(0.229–1.059)
R0 resection
0.733
0.906
(0.516–1.593)
Systemic Ctx
0.462
0.680
(0.244–1.899)
DISCUSSION Current accepted standard of care for advanced gastric cancer without distant metastases consists of a multimodality approach with neoadjuvant systemic chemotherapy, followed by radical surgery and adjacent adjuvant systemic treatment.1,3,4,7 Despite limitations in
1,0
CRS-HIPEC No-PC CRS-HIPEC-censored No-PC-censored
0,8
p=0,622 Survival
Applying univariate analysis in a first step of analysis, younger age (\56 years) and HIPEC performed had a significant positive effect on survival among all tested variables (Table 2). Survival rates were higher with systemic chemotherapy, but this difference was not significant (p = 0.462). Multivariate analysis using a cox regression model was performed to determine which variables were most strongly correlated with survival. All clinical variables that were close to significance (p \ 0.10) in univariate analysis were included in this analysis. HIPEC (p = 0.008) and age \56 years (p = 0.05) were again the two clinical factors associated with better survival. The presence of lymph node metastasis had a strong negative effect on survival, but the difference was not significant in the multivariate model (p = 0.07). Finally, a matched pair analysis between the CRSHIPEC group and the No-PC group was performed to determine whether the intraoperative use of HIPEC had a positive effect on overall survival after gastrectomy by local ‘‘eradication’’ of PC. The median survival time after gastrectomy was similar in both groups with 18.1 months (95 % CI 10.1–26.0 months) in patients receiving HIPEC compared with 21.8 months (95 % CI 8.0–35.5 months) in patients operated for gastric cancer without PC. Hence, survival rates were equal in both groups in the matchedpairs approach (Fig. 3). After 2 years, approximately onethird of the patients were alive in both groups. The 5-year survival rate was 11.9 % in CRS-HIPEC patients versus 12.1 % in No-PC patients. Thus, taken together, patients with advanced gastric cancer without PC showed no survival benefit to patients with limited PC treated with HIPEC (p = 0.622; Fig. 3).
0,6
0,4
0,2
0,0 0
20
40
60
80
Time after gastrectomy (months) 1-yearsurvival
2-yearssurvival
3-yearssurvival
5-yearssurvival
HIPEC (n=38)
65.1%
43.0%
31.8%
11.9%
No-PC (n=38)
71.0%
47.0%
40.3%
12.1%
FIG. 3 a Kaplan–Meier analysis of matched pairs with advanced gastric cancer without PC and patients with advanced gastric cancer with PC treated with HIPEC. No significant difference can be observed in terms of OS between the two groups (p = 0.622). b Survival rates after gastrectomy of patients with advanced gastric cancer with PC treated with HIPEC versus patients with advanced gastric cancer without evidence of PC
overall survival and high recurrence rates, even patients with locally advanced cancer and extended lymphatic spread are considered potentially curable and therefore are treated by this radical approach. However, once PC is diagnosed, the same primary tumor is quickly considered metastatic and noncurable and patients are excluded from extended therapy options limiting their treatment approach to palliative systemic chemotherapy and best supportive care. This traditional perception of PC as an expression of metastatic spread determines PC as incurable, even when its manifestation is locally limited or associated to an early tumor stage. Opponents of such characterisation of PC as a feature of
CRS-HIPEC Prolongs Survival but is Not Curative for Patients
systemic disease suggest it to be a result of locoregional extension of the primary cancer into the peritoneal cavity. Following this school of thought, the risk perception of PC may be equalized to a locally advanced primary tumor or locoregional lymphadenopathy, two disease manifestations traditionally managed with curative intent. Recently, this has been considered particularly true when the overall PC tumor load is low—with a PCI \10. Evidence justifying the treatment of gastric PC with cytoreductive surgery and HIPEC is in flux and is not yet entirely convincing applying highest criteria of evidence. Most published trials focused on proving the benefit of combining CRS with HIPEC, demonstrating the superiority of HIPEC compared with surgical resection only in the treatment of PC from gastric cancer.8,9 Based on this study concept, Yang et al. were able to prospectively show a significant survival benefit for patients receiving CRS and HIPEC compared with those treated by CRS alone.10 Analysing our two patient groups with PC, who underwent either CRS and HIPEC or standard (systemic) therapy only after gastrectomy, we also found a survival advantage for patients treated by gastrectomy plus CRS-HIPEC versus gastrectomy plus systemic chemotherapy by retrospective analysis. Thus, our data support the benefit of additional HIPEC for the setting of radical surgical elimination of peritoneal metastatic gastric cancer. Compared with Yang et al. (OS CRS group: 6.5 months; OS CRS ? HIPEC: 11 months) and other survival data reported in previous studies, our patient cohort undergoing CRS-HIPEC was associated with an improved median overall survival.8–10 This difference is likely a selection bias with high rates of CCR 0-1 resections in our study population, as CCR 0-1 resection status has been demonstrated as a strong prognostic factor for better survival in multivariate analysis. Supporting this, Glehen et al. also reported median OS of 9 months for the CRS-HIPEC group compared with 15 months when completeness of cytoreduction was achieved.11 The absence of PC in the majority of cases justifies the current standard of care consisting of systemic pre- and postoperative chemotherapy and radical gastrectomy plus D2-lymphadenectomy.7 Nevertheless, our data clearly demonstrate that the survival of advanced gastric cancer patients with PC treated by CRS and HIPEC is not significantly different compared with the gastric cancer group without PC, although PC is assumed to be the strongest negative predictive factor.12,13 The clinical outcome of advanced gastric cancer patients without PC in our cohort is consistent with generally reported survival rates.14 In addition, due to matching, tumor stages were similar in both groups analyzed, excluding bias from primary tumor stage as good as possible in the retrospect.
Despite the efficacy of HIPEC as an adjunct to gastrectomy, we were unable to identify long-term survivors in the two PC groups, underlining the fact that PC from gastric cancer remains a bleak prognosis. The same is true for advanced lymphatic spread. As expected, patients treated with gastrectomy plus CRS and intraoperative HIPEC have better survival outcomes than patients with PC receiving palliative therapy only. The poor survival data for the palliative group in our analysis are in line with previous reports and are also partly an expression of selection bias against surgery in this surgical paper.15 On the other hand, prospective, randomized, controlled trials of patients with advanced gastric cancer undergoing systemic chemotherapy only also have shown limited efficacy. Patients receiving trastuzumab in combination with chemotherapy within the ToGa-trial for advanced gastric cancer had a median survival time of only 14 months. Only the subgroup of patients with strong expression of HER2protein showed comparable median survival (17 months) to our patient cohort receiving the multimodal concept of gastrectomy with CRS-HIPEC. Unfortunately, no prospective data are available that analyze the true survival benefit of CRS and HIPEC compared with the standard of care for patients with PC from gastric cancer. Current, ongoing, prospective, clinical trials, such as the GASTRIPEC- and GASTRICHIPtrials are still recruiting. Initial results are expected to be published shortly.16,17 Also true for our present study, the majority of published trials in this context are based on retrospective data with significant heterogeneity in the patient groups included. The inherent selection bias cannot be overcome by these trials. Due to the small survival gain after CRS and HIPEC, together with significant perioperative morbidity and devastating recurrence rates, many surgeons hesitate in supporting a radical, multimodal treatment concept when PC is evident in gastric cancer patients. Nevertheless, our results support the vision of a progressive perception of PC in gastric cancer, because it is not the only predictor of poor survival, especially compared with lymphatic spread. Without doubt, in the absence of a breakthrough systemic treatment, PC will remain associated with poor outcome and CRS-HIPEC is a high-risk treatment concept. However, our observation that patients without PC had no better survival compared with patients with aggressively treated PC when matching for tumor stage of the primary tumor challenges the standard-of-care as the only justifiable concept for advanced gastric cancer patients, particularly for patients with low PC loads (PCI \10) that can be subjected to complete cytoreduction (CCR-0).
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CONCLUSIONS Survival of gastric cancer patients with PC treated with gastrectomy and CRS/HIPEC is not significantly different from stage-matched patients without PC receiving gastrectomy and standard therapy. Aggressive, multimodal treatment of PC of gastric cancer with CRS and HIPEC thus can be justified (in particular for patients with a PCI \10), because it is associated with improved survival, albeit it offers no long-term cure. REFERENCES 1. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29(13):1715–21. 2. Waddell T, Verheij M, Allum W, et al. Gastric cancer: ESMOESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:vi57–63. 3. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Eng J med. Jul 6 2006;355(1):11–20. 4. Ronellenfitsch U, Schwarzbach M, Hofheinz R, et al. Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus. Cochrane Database Syst Rev. 2013;5:CD008107. 5. Burke EC, Karpeh MS, Conlon KC, Brennan MF. Laparoscopy in the management of gastric adenocarcinoma. Ann Surg. 1997;225(3):262–7. 6. De Andrade JP, Mezhir JJ. The critical role of peritoneal cytology in the staging of gastric cancer: an evidence-based review. J Surg Oncol. 2014;110(3):291–7. 7. Okines A, Verheij M, Allum W, Cunningham D, Cervantes A, Group EGW. Gastric cancer: ESMO Clinical Practice Guidelines
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