Johan L. Dikken

Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS)

BackgroundRadical surgery is the cornerstone in the treatment of resectable gastric cancer. The Intergroup 0116 and MAGIC trials have shown benefit of postoperative chemoradiation and perioperative chemotherapy, respectively. Since these trials cannot be compared directly, both regimens are evaluated prospectively in the CRITICS trial. This study aims to obtain an improved overall survival for patients treated with preoperative chemotherapy and surgery by incorporating radiotherapy concurrently with chemotherapy postoperatively.Methods/designIn this phase III multicentre study, patients with resectable gastric cancer are treated with three cycles of preoperative ECC (epirubicin, cisplatin and capecitabine), followed by surgery with adequate lymph node dissection, and then either another three cycles of ECC or concurrent chemoradiation (45 Gy, cisplatin and capecitabine). Surgical, pathological, and radiotherapeutic quality control is performed. The primary endpoint is overall survival, secondary endpoints are disease-free survival (DFS), toxicity, health-related quality of life (HRQL), prediction of response, and recurrence risk assessed by genomic and expression profiling. Accrual for the CRITICS trial is from the Netherlands, Sweden, and Denmark, and more countries are invited to participate.ConclusionResults of this study will demonstrate whether the combination of preoperative chemotherapy and postoperative chemoradiotherapy will improve the clinical outcome of the current European standard of perioperative chemotherapy, and will therefore play a key role in the future management of patients with resectable gastric cancer.Trial registrationclinicaltrials.gov NCT00407186

Impact of the Extent of Surgery and Postoperative Chemoradiotherapy on Recurrence Patterns in Gastric Cancer

PURPOSE The Intergroup 0116 trial has demonstrated that postoperative chemoradiotherapy (CRT) improves survival in gastric cancer. We retrospectively compared survival and recurrence patterns in two phase I/II studies evaluating more intensified postoperative CRT with those from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients between D1 and D2 lymphadenectomy. PATIENTS AND METHODS Survival and recurrence patterns of 91 patients with adenocarcinoma of the stomach who had received surgery followed by radiotherapy combined with fluorouracil and leucovorin (n = 5), capecitabine (n = 39), or capecitabine and cisplatin (n = 47) were analyzed and compared with survival and recurrence patterns of 694 patients from the DGCT (D1, n = 369; D2, n = 325). For both groups, the Maruyama Index of Unresected Disease (MI) was calculated and correlated with survival and recurrence patterns. RESULTS With a median follow-up of 19 months in the CRT group, local recurrence rate after 2 years was significantly higher in the surgery only (DGCT) group (17% v 5%; P = .0015). Separate analysis of CRT patients who underwent a D1 dissection (n = 39) versus DGCT-D1 (n = 369) showed fewer local recurrences after chemoradiotherapy (2% v 8%; P = .001), whereas comparison of CRT-D2 (n = 25) versus DGCT-D2 (n = 325) demonstrated no significant difference. CRT significantly improved survival after a microscopically irradical (R1) resection. The MI was found to be a strong independent predictor of survival. CONCLUSION After D1 surgery, the addition of postoperative CRT had a major impact on local recurrence in resectable gastric cancer.

Differences in outcomes of oesophageal and gastric cancer surgery across Europe

In several European countries, centralization of oesophagogastric cancer surgery has been realized and clinical audits initiated. The present study was designed to evaluate differences in resection rates, outcomes and annual hospital volumes between these countries, and to analyse the relationship between hospital volume and outcomes.

Increased incidence and survival for oesophageal cancer but not for gastric cardia cancer in the Netherlands

INTRODUCTION A worldwide increasing incidence is seen for oesophageal adenocarcinoma, but not for oesophageal squamous cell carcinoma (SCC) and gastric cardia adenocarcinoma. Purposes of the current study were to evaluate the changing incidence rates of oesophageal and gastric cardia cancer, and to assess survival trends. PATIENTS AND METHODS Patients diagnosed with oesophageal adenocarcinoma (N=12,195) or SCC (N=9046), or gastric cardia adenocarcinoma (N=9900) between 1989 and 2008 in the Netherlands were included. Changes in European Standard Population (ESP) and relative survival over time were evaluated. RESULTS Incidence rates for oesophageal adenocarcinoma increased in males (+7.5%, P<0.001) and females (+5.2%, P<0.001), while the incidence for oesophageal SCC remained stable in males (-0.2%, P=0.6) and slightly increased in females (+1.7%, P=0.001). The incidence for gastric cardia cancer decreased in males (-1.2%, P<0.006), and remained stable in females (-0.2%, P=0.7). Five-year survival for both M0 and M1 oesophageal carcinoma doubled over the last 20 years. No significant changes in survival were found for M0 and M1 gastric cardia carcinoma. DISCUSSION In the Netherlands, a rising incidence is seen for oesophageal adenocarcinoma, but not for gastric cardia adenocarcinoma. This finding most likely reflects true changes in disease burden, rather than being the result of changes in diagnosis or classification. The increased survival for oesophageal carcinoma can be attributed to centralisation of surgery, and an increased use of multimodality therapy, factors hardly acknowledged for gastric cancer.

Effect of hospital volume on postoperative mortality and survival after oesophageal and gastric cancer surgery in the Netherlands between 1989 and 2009.

BACKGROUND High hospital volume is associated with better outcomes after oesophagectomy and gastrectomy. In the Netherlands, a minimal volume standard of 10 oesophagectomies per year was introduced in 2006. For gastrectomy, no minimal volume standard was set. Aims of this study were to describe changes in hospital volumes, mortality and survival and to explore if high hospital volume is associated with better outcomes after oesophagectomy and gastrectomy in the Netherlands. METHODS From 1989 to 2009, 24,246 patients underwent oesophagectomy (N = 10,025) or gastrectomy (N = 14,221) in the Netherlands. Annual hospital volumes were defined as very low (1-5), low (6-10), medium (11-20), and high (≥ 21). Volume-outcome analyses were performed using Cox regression, adjusting for year of diagnosis, case-mix and the use of multi-modality treatment. RESULTS From 1989 to 2009, the percentage of patients treated in high-volume hospitals increased for oesophagectomy (from 7% to 64%), but decreased for gastrectomy (from 8% to 5%). Six-month mortality (from 15% to 7%) and 3-year survival (from 41% to 52%) improved after oesophagectomy, and to a lesser extent after gastrectomy (6-month mortality: 15%-10%, three-year survival: 55-58%). High hospital volume was associated with lower 6-month mortality (hazard ratio (HR) 0.48, P<0.001) and longer 3-year survival (HR 0.77, P<0.001) after oesophagectomy, but not after gastrectomy. CONCLUSIONS Oesophagectomy was effectively centralised in the Netherlands, improving mortality and survival. Gastrectomies were mainly performed in low volumes, and outcomes after gastrectomy improved to a lesser extent, indicating an urgent need for improvement in quality of surgery and perioperative care for gastric cancer in the Netherlands.

Gastric cancer: Decreasing incidence but stable survival in the Netherlands

Abstract Background. Gastric cardia and non-cardia cancer exhibit differences in biological and epidemiological features across the world. The aims of this study were to analyze trends in incidence, stage distribution, and survival over a 20-year period in the Netherlands, separately for both types of gastric cancer. Methods. Data on all patients with a diagnosis of gastric cancer in the period 1989–2008 were obtained from the nationwide Netherlands Cancer Registry. Time trends in incidence [analyzed as European Standard Rate per 100 000 (ESR)] and relative survival were separately analyzed for cardia and non-cardia gastric cancer. Results. A total of 47 295 patients were included. Incidence rates per 100 000 for cardia cancer declined from 5.7 to 4.3 for males and remained stable for females (1.2). For non-cardia cancer, the incidence in males declined from 25 to 14 and in females from 10 to 7. Proportional incidence in stage IV cardia and non-cardia cancer increased in 2004–2008 (cardia 32–42%, non-cardia 33–45%). Five-year survival rates for stage I–III and X (unknown) remained stable (cardia cancer: 20%, non-cardia gastric cancer: 31%). Five-year survival for stage IV disease was 1.9% and 1.0% for cardia and non-cardia gastric cancer. Conclusion. The incidence of gastric cancer in the Netherlands markedly decreased over the past decades, in particular of non-cardia cancer. Survival remained dismal. Improvement of survival remains a challenge for the multidisciplinary team involved in gastric cancer treatment.

Influence of hospital type on outcomes after oesophageal and gastric cancer surgery

Outcomes after oesophagectomy and gastrectomy vary considerably between hospitals. Possible explanations include differences in case mix, hospital volume and hospital type. The present study examined the distribution of oesophagectomies and gastrectomies between hospital types in the Netherlands, and the relationship between hospital type and outcome.

Lymph node dissection in resectable advanced gastric cancer.

The extent of surgery for gastric cancer has been debated since Billroth performed his first gastrectomy in 1881. This review gives an overview of the available literature on the extent of gastrectomy and lymphadenectomy for advanced resectable gastric cancer. Subtotal gastrectomy is associated with lower morbidity and mortality compared with total gastrectomy, without compromising long-term survival. However, a positive resection margin decreases the chance of curation. Frozen section examination may prevent this. For poorly differentiated singlet ring cell tumors, there may be an argument to perform a total gastrectomy in all cases. In 1981, the Japanese Research Society for the Study of Gastric Cancer provided guidelines for the standardization of surgical treatment and pathological evaluation of gastric cancer. Since then, D2 lymph node dissections have become the standard of care in Japan. Because of the superior stage-specific survival rates in Japan, a D2 dissection was evaluated in several Western randomized controlled trials, but no survival benefit was found for a D2 over a D1 dissection. This might be explained by the increased mortality in the D2 dissection groups which might be the result of a standard pancreaticosplenectomy and low experience with D2 dissections. Adding the removal of the para-aortic nodes to a D2 dissection does not further improve survival. The removal of lymph node stations 10 and 11 by splenectomy showed an increased morbidity, no survival benefit, and a very poor prognosis if lymph nodes were affected. Therefore, pancreaticosplenectomy should only be performed in cases of tumor invasion into these organs. A D2 dissection without routine splenectomy and pancreatic tail resection in experienced hands should be considered standard of care for advanced resectable gastric cancer, both in Asian and in Western patients. Centralization and auditing may further improve outcomes after gastrectomy.

Changes in treatment patterns and their influence on long-term survival in patients with stages I-III gastric cancer in The Netherlands.

Studies investigating perioperative chemotherapy and/or radiotherapy changed the treatment of curable gastric cancer in The Netherlands. These changes were evaluated including their influence on survival. Data on patients diagnosed with gastric cancer from 1989 to 2009 were obtained from The Netherlands Cancer Registry. Changes over time in surgery and administration of perioperative chemotherapy, 30‐day mortality, 5‐year survival and adjusted relative excess risk (RER) of dying were analyzed with multivariable regression for cardia and noncardia cancer. In stages I and II disease, most patients underwent surgery. Since 2005, more patients are treated with (neo)adjuvant chemotherapy. Postoperative mortality ranged from 1% to 7% and 0.4% to 12.2% in cardia and noncardia cancer (<55 to 75+ years). Five‐year survival for cardia cancer and noncardia cancer stages I–III and X (unknown stage) was 33% and 50% (2005–2008). The RER of dying was associated with period of diagnosis, age, gender, region, stage, (neo)adjuvant chemotherapy in case of cardia cancer and type of gastric resection in case of noncardia cancer. Administration of (neo)adjuvant chemotherapy has increased. No improvement in long‐term survival could yet be seen, though it is still too early to expect an improvement in survival as a result of the use of chemotherapy.

Quality of Care Indicators for the Surgical Treatment of Gastric Cancer: A Systematic Review

BackgroundQuality assurance is increasingly acknowledged as a crucial factor for the (surgical) treatment of gastric cancer. The purpose of the current study was to define a minimum set of evidence-based quality of care indicators for the surgical treatment of locally advanced gastric cancer.MethodsA systematic review of the literature published between January 1990 and May 2011 was performed, using search terms on gastric cancer, treatment, and quality of care. Studies were selected based on predefined selection criteria. Potential quality of care indicators were assessed based on their level of evidence and were grouped into structure, process, and outcome indicators.ResultsA total of 173 articles were included in the current study. For structural measures, evidence was found for the inverse relationship between hospital volume and postoperative mortality as well as overall survival. Regarding process measures, the most common indicators concerned surgical technique, perioperative care, and multimodality treatment. The only outcome indicator with supporting evidence was a microscopically radical resection.ConclusionsAlthough specific literature on quality of care indicators for the surgical treatment of locally advanced gastric cancer is limited, several quality of care indicators could be identified. These indicators can be used in clinical audits and other quality assurance programs.