Background: Previous studies investigating whether metastatic lymph node count is a relevantprognostic factor in pathological N1 non-small cell lung cancer (NSCLC), showed conflictingresults.... Show moreBackground: Previous studies investigating whether metastatic lymph node count is a relevantprognostic factor in pathological N1 non-small cell lung cancer (NSCLC), showed conflictingresults. Hypothesizing that outcome may also be related to histological features, wedetermined the prognostic impact of single versus multiple metastatic lymph nodes in differenthistological subtypes for patients with stage II-N1 NSCLC.Methods: We performed a retrospective cohort study using data from the Netherlands CancerRegistry, including patients treated with a surgical resection for stage II-N1 NSCLC (TNM 7thedition) in 2010–2016. Overall survival (OS) was assessed for patients with single (pN1a) andmultiple (pN1b) metastatic nodes. Using multivariable analysis, we compared OS betweenpN1a and pN1b in different histological subtypes.Results: After complete resection of histologically proven stage II-N1 NSCLC, 1309 patientswere analyzed, comprising 871 patients with pN1a and 438 with pN1b. The median numberof pathologically examined nodes (N1 + N2) was 9 (interquartile range 6–13). Five-year OS was53% for pN1a versus 51% for pN1b. In multivariable analysis, OS was significantly differentbetween pN1a and pN1b (HR 1.19, 95% CI 1.01–1.40). When stratifying for histology, the prognosticimpact of pN1a/b was only observed in adenocarcinoma patients (HR 1.44, 95% CI1.15–1.81).Conclusion: Among patients with stage II-N1 adenocarcinoma, the presence of multiple metastaticnodes had a significant impact on survival, which was not observed for other histologicalsubtypes. If further refinement as to lymph node count will be considered for incorporationinto a new staging system, evaluation of the role of histology is recommended. Show less
The tumor–stroma ratio (TSR) has previously been found to be a strong prognostic parameter in primary breast cancer tumors.Since the presence of tumor cells in lymph nodes is important for clinical... Show moreThe tumor–stroma ratio (TSR) has previously been found to be a strong prognostic parameter in primary breast cancer tumors.Since the presence of tumor cells in lymph nodes is important for clinical decision making, the influence of TSR in the primarybreast tumor combined with the TSR in tumor-positive lymph nodes on prognosis was evaluated. Women with invasive breastcancer without distant metastasis who underwent an axillary lymph node dissection between 1985 and 1994 at the LeidenUniversity Medical Center were retrospectively analyzed. TSR assessment was performed on hematoxylin and eosin stainedtissue slides. In total, 87 (45.5%) primary tumors were scored as stroma-low and 104 (54.5%) as stroma-high. Patients with ahigh stromal percentage in the primary tumors had a statistically significant worse relapse free period (RFP) compared tostroma-low tumors (HR 1.97, 95% CI 1.37–2.82, p < 0.001). A total number of 915 lymph nodes were assessed for TSR. In101 (52.9%) patients, heterogeneity was observed between stroma percentage category in primary tumor and lymph nodes.The combination of TSR of the primary tumor combined with TSR of tumor-positive lymph nodes strengthened each other asindependent prognostic parameter for RFP (p = 0.019). Patients with primary tumor stroma-low/lymph nodes stroma-lowtumors showed strongly improved RFP rates compared to patients with primary tumor stroma-high/lymph node stroma-hightumors with 10-year percentages of 58 versus 8%, respectively. Assessing the TSR on tumor-positive lymph nodes can provideadditional prognostic information. Stromal activation strongly differs between primary tumors and lymph node metastasis. Show less
Research described in this thesis focuses on several aspects of gastric cancer care: staging and prognostication, multimodality treatment, and surgical quality assurance. PART I - STAGING AND... Show moreResearch described in this thesis focuses on several aspects of gastric cancer care: staging and prognostication, multimodality treatment, and surgical quality assurance. PART I - STAGING AND PROGNOSTICATION Cancer staging is one of the fundamental activities in oncology.6,7 For over 50 years, the TNM classification has been a standard in classifying the anatomic extent of disease.8 In order to maintain the staging system relevant, the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) have collaborated on periodic revisions of this staging system, leading to the 7th edition in 2010.65 In Chapter 2, differences between the 6th and 7th edition TNM classification for gastric cancer are described, and both staging systems are compared with regards to complexity and predictive accuracy. In the 7th edition TNM classification, nodal status cut-off values were changed, leading to a more even distribution for the redefined nodal classification groups. This increased the predictive accuracy of N-classification. Overall, the TNM staging system became more complex, with an increase in the number of TNM groupings from 56 to 80, which did not result in an increased predictive accuracy. Future refinements of the TNM-classification should consider whether increased complexity is balanced by improved prognostic accuracy. Another change that was incorporated in the 7th edition TNM classification was the addition of tumor grade as an independent determinant of stage grouping in early stage tumors. With the significantly lower prognosis of poorly differentiated early stage adenocarcinomas, these tumors might become candidate for neoadjuvant therapy, given an accurate identification of these tumors with preoperative staging. In Chapter 3, the accuracy of preoperative histopathologic grading in adenocarcinomas of the gastroesophageal junction (GEJ) was evaluated. The overall accuracy of tumor grade assessment was 73%. However, in early stage tumors the sensitivity to detect a poorly differentiated tumor was only 43%, and 21% of patients with an early stage GEJ tumor were assigned to an incorrect stage/prognostic group based on preoperative tumor grading. Caution should therefore be exhibited in staging patients with esophageal adenocarcinoma based on preoperative biopsy data. Although the TNM classification can be used to assess a patient__s prognosis, tools for individual patient prognostication have been developed that significantly outperform the TNM-classification in prognostic accuracy. For gastric cancer, a nomogram has been developed based on a single US-institution database,12,13 and has been validated in several international patient cohorts.14-16 Chapter 4 describes the development of a new gastric cancer nomogram that not only can predict survival for patients directly after an R0 gastrectomy, but also for patients alive at time points after surgery. This conditional probability of survival nomogram was highly discriminating (concordance index: 0.772), and surviving one, two, or three years from surgery showed a median improvement of 5-year disease-specific survival of 7.2%, 19.1%, and 31.6%, as compared to the baseline prediction directly after surgery. This nomogram was based on variables available directly after surgery, while variables available with follow-up (such as weight loss and performance status) did not further improve the predictive accuracy of this nomogram. In Chapter 5, the performance of the original gastric cancer nomogram, which was based on patients who underwent surgery without multimodality therapy, was assessed in a group of patients who received postoperative chemoradiotherapy after an R0 resection for gastric cancer. The nomogram significantly underpredicted 5-year survival for patients who received postoperative chemoradiotherapy, indicating a benefit in survival for patients who receive postoperative chemoradiation after an R0 resection for gastric cancer. Furthermore, this study stresses the need for updating nomograms that incorporate multimodality therapy use. PART II - MULTIMODALITY TREATMENT Over the past decade, many trials have been performed in which the effect of multimodality treatment on survival for resectable gastric cancer was evaluated. In Chapter 6, an overview of the literature on the treatment of gastric cancer is presented, and the available multimodality strategies are discussed. Currently accepted regimens include postoperative monochemotherapy with S-1 in Asia,66 and perioperative chemotherapy and postoperative chemoradiotherapy in the Western world.57,58 In Chapter 7, patterns of recurrence and survival of patients who received postoperative chemoradiotherapy were compared to recurrence and survival patterns of patients who only underwent surgery. The local recurrence rate was significantly lower in the chemoradiotherapy group (5% versus 17%, P = 0.0015). Subgroup analysis revealed that this difference was even stronger in patients who underwent a gastrectomy with a limited (D1) lymph node dissection (2% versus 18%, P = 0.001), while no difference was found for patients who underwent an extended (D2) lymph node dissection. Additional analysis with prolonged follow-up showed a higher 2-year overall survival for patients who received postoperative chemoradiotherapy after a D1 lymphadenectomy compared to surgery alone, and no difference in overall survival for patients who received a D2 dissection. Postoperative chemoradiotherapy was also significantly associated with higher two-year overall survival for patients who underwent a microscopically irradical (R1) resection (66% versus 29%, P = 0.02). Results from this study indicate that, especially after a gastrectomy with a limited lymph node dissection, postoperative chemoradiotherapy has a major impact on local recurrence and overall survival. Postoperative chemoradiotherapy should be offered to patients who undergo a microscopically irradical (R1) resection. In Chapter 8, the results of a study on lymph node yield after gastric cancer resections are described. While it is suggested that more than 15 lymph nodes (LNs) should be evaluated for accurate staging of gastric cancer, LN yield in Western countries is generally low. The effect of preoperative chemotherapy on LN yield in gastric cancer is unknown. In this study, LN yields of patients who received preoperative chemotherapy and patients who only underwent surgery were compared. Preoperative chemotherapy was not associated with a decrease in LN yield, indicating that evaluating more than 15 LNs after gastrectomy is feasible, also after administration of preoperative chemotherapy. In Chapter 9, the final chapter of part II of this thesis, the study protocol of the currently accruing Dutch-Swedish-Danish CRITICS trial is described. This trial was initiated to determine which of the two currently used standard regimens for the multimodality treatment of gastric cancer in the Western world, postoperative chemoradiotherapy, or perioperative chemotherapy, should be preferred. In this trial, all patients receive three cycles of preoperative ECC (epirubicin, cisplatin, and capecitabine), followed by D1+ surgery (D2 dissection without splenectomy or pancreatectomy). Postoperative therapy consists of another three cycles of ECC, or chemoradiotherapy with capecitabine and cisplatin without epirubicine. Results of this study will play a key role in the future management of patients with resectable gastric cancer. PART III - SURGICAL QUALITY ASSURANCE As an introduction to part III of this thesis, in Chapter 10, the results of a systematic review of the literature on quality of care indicators for gastric cancer surgery are described. The availability of specific literature on quality of care indicators was limited, but several indicators could be identified in more general literature on gastric cancer surgery. High hospital volume was found to be strongly related to lower postoperative mortality and higher long-term survival. Several quality indicators regarding operative technique were identified, including the performance of an extended lymphadenectomy, avoiding a routine spleen and pancreatic tail resection, and the use of a pouch reconstruction. Free resection margins were also found to be strongly associated with improved long-term survival. In Chapter 11 and Chapter 12, incidence and survival patterns for tumors of the esophagus, GEJ, and stomach in the Netherlands over the past 20 years are described. While the incidence of esophageal adenocarcinoma has doubled, the incidence of both tumors of the GEJ and stomach has decreased. These findings most likely reflect true changes in disease burden, rather than being the result of changes in diagnosis or reclassification. The increasing incidence of esophageal adenocarcinoma can be attributed to the increasing incidence of obesity and gastroesophageal reflux disease.67,68 Over the study period, five-year survival for non-metastatic esophageal cancer strongly improved (12% to 25% for adenocarcinoma, 12% to 19% for squamous cell carcinoma), while five-year survival for non-metastatic GEJ cancer (20%) and stomach cancer (32%) remained stable. In Chapter 13, patterns of care for gastric cancer in the Netherlands over the past 20 years are described. Whereas resection rates for stage I-III gastric cancer have remained stable at about 85%, the use of preoperative and/or postoperative chemotherapy has strongly increased since 2005. In 2008, nearly 40% of the patients with stage I-III gastric cancer received preoperative or postoperative chemotherapy with curative intent, and it is likely that since then, this percentage has further increased. In Chapter 14, the results of a study on hospital volumes, mortality, and long-term survival for esophagogastric cancer surgery in the Netherlands between 1989 and 2009 are described. In the Netherlands, a minimum hospital volume standard of at least 10 esophagectomies per year was introduced in 2006, while during the study period, no such standard was present for gastrectomies. During the study period, esophagectomy was effectively centralized in the Netherlands, and in 2009, 64% of all esophagectomies were performed in annual volumes of __21/year. Gastrectomy has not been centralized, and in 2009 only 5% of all gastrectomies were performed in annual volumes of __21/year. Whereas short-term and long-term survival after esophagectomy and gastrectomy improved over the years, this improvement was significantly stronger for esophagectomy. High hospital volume was associated with lower 6-month mortality (HR 0.48, P < 0.001) and longer 3-year survival (HR 0.77, P < 0.001) after esophagectomy, but not after gastrectomy. However, for gastrectomy, the number of high volume resections in the current study was too low to detect a statistical significant difference in outcomes when compared with low volume resections. This study indicates an urgent need for improvement in the treatment of resectable gastric cancer in the Netherlands. Chapter 15 describes the results of a study on the effect of hospital type on outcomes after esophagectomy and gastrectomy in the Netherlands. Hospitals were categorized into university hospitals, teaching non-university hospitals, and non-teaching hospitals. Three-month mortality after esophagectomy in university hospitals was 2.5%, compared to above 4% in non-university hospitals (P = 0.006). After gastrectomy, three-month mortality was 4.9% in university hospitals, and 8.7% in non-university hospitals (P < 0.001). Both after esophagectomy and gastrectomy, three-year survival was higher in university hospitals compared to non-university hospitals. No differences in mortality or survival were found between teaching and non-teaching non-university hospitals. However, when analyzing differences between individual hospitals, there were non-university hospitals with excellent outcomes. Therefore, it can be concluded that centers of excellence can not be designated solely by hospital type, and that detailed information on case-mix and outcomes is needed to identify centers of excellence. In Chapter 16, the results of an international study on esophagogastric cancer surgery between 2004 and 2009 in several European countries are described. Differences in resection rates, postoperative mortality, survival and hospital volumes were compared between the Netherlands, Sweden, Denmark, and England. In the Netherlands, postoperative mortality was average after esophagectomy (4.6%), but significantly higher after gastrectomy (6.9%) when compared to the other countries. Although increasing hospital volume was associated with lower 30-day mortality both after esophagectomy and gastrectomy, differences in outcomes between countries could not just be explained by existing differences in hospital volumes. To further investigate the differences in outcomes, a European upper GI audit is currently initiated. Show less
