Population-based survival rates after curative surgical and non-surgical treatment of stage III NSCLC since 2017.

OBJECTIVES: In stage III non-small cell lung cancer (NSCLC), curative treatment approaches used to include neoadjuvant therapy followed by surgery, and definitive chemoradiotherapy followed by consolidation durvalumab (CRT-ICI). Surgical strategies included either neoadjuvant chemotherapy (CTx-surg) or chemoradiotherapy (CRT-surg). We studied the outcomes of these three radical intent strategies in the Netherlands Cancer Registry (NCR) for patients diagnosed from 2017 to 2021. MATERIALS AND METHODS: Patients with clinical stage III NSCLC (TNM edition 8) were identified in the NCR after excluding patients with known driver mutations, ECOG performance status >=2, N3-disease and those undergoing sequential chemoradiotherapy or single modality/palliative treatments. Overall survival (OS) was calculated from date of surgery or start of durvalumab. RESULTS: Treatments delivered were CRT-ICI (n = 1016 patients), CRT-surg (n = 166) and CTx-surg (n = 111). The surgical series comprised 224 lobectomies, 21 bilobectomies and 32 pneumonectomies, with a 90-day postoperative mortality rate of 3.3 %. Use of CRT-surg decreased steeply after 2018, when durvalumab became fully reimbursed, and use of CRT-ICI increased. Three-year OS was better following CRT-surg (78.7 %) compared to CTx-surg (66.7 %) or CRT-ICI (63.2 %). After controlling for age, ECOG performance status and histology, the hazard ratios for CRT-surg and CTx-surg were 0.66 (95 % CI 0.47-0.91) and 0.82 (95 % CI 0.58-1.17), respectively, compared to CRT-ICI. CONCLUSION: Population survivals after curative strategies for clinical stage III NSCLC in The Netherlands exceed those reported historically for both surgical and non-surgical approaches. Use of surgery decreased from 2018 following the formal reimbursement of durvalumab. While variations in case-mix hamper comparison between curative treatment strategies, there is a clear need for randomized studies in subgroups with potentially resectable disease.

Prognostic impact of KRAS mutation status for patients with stage IV adenocarcinoma of the lung treated with first-line pembrolizumab monotherapy.

OBJECTIVES: Monotherapy with pembrolizumab is the preferred first-line treatment for metastatic non-small cell lung cancer with programmed death-ligand 1 (PD-L1) expression ≥50 %, without targetable oncogenic drivers. Although targeted therapies are in development for patients with specific Kirsten rat sarcoma (KRAS) mutations, these are not available in daily care yet. It is not clear whether there is a difference in survival on first-line pembrolizumab for patients with a high PD-L1 status with or without a KRAS mutation. We aim to compare this survival based on real-world data. MATERIALS AND METHODS: This is a real-world retrospective population-based study using data from the Netherlands Cancer Registry. We selected patients with stage IV lung adenocarcinoma with PD-L1 expression ≥50 % diagnosed between January 2017 and December 2018, treated with first-line pembrolizumab. Patients with EGFR mutations, ALK translocations or ROS1 rearrangements were excluded. The primary outcome parameter was overall survival. RESULTS: 388 (57 %) of 595 patients had a KRAS mutation. KRAS was seen more frequently in women than in men (65 % versus 49 % respectively, p < 0.001). The median overall survival was 19.2 months versus 16.8 months for patients with and without KRAS mutation, respectively (p = 0.86). Multivariable analysis revealed WHO performance score, number of organs with metastases and PD-L1 percentage as independent prognostic factors. KRAS mutation status had no prognostic influence (hazard ratio = 1.03, 95 % CI 0.83-1.29). CONCLUSION: The survival of KRAS mutated versus KRAS wild-type lung adenocarcinoma patients, treated with first-line pembrolizumab monotherapy, is similar, suggesting that KRAS has no prognostic value with respect to treatment with pembrolizumab.

[The effects of smoking on health: growth of knowledge reveals even grimmer picture]. / De gezondheidseffecten van roken.

- In this article we give a short overview of new insights into the effects of smoking on health, both on smokers themselves and on those who are exposed to other people's tobacco smoke.- The number of diseases and conditions that are known to be caused by active smoking has now risen to over thirty.- The risk of premature death is not, as previously thought, twice as high in smokers as in non-smokers, but actually three times as high.- Passive smoking too has been shown to have a whole range of negative effects on health.- Further, the causal mechanisms of, amongst other things, the development of cancer, ischaemic heart disease and nicotine dependence under the influence of smoking have been largely unravelled.- Various issues require further investigation; these include the effect of smoking on psychological health and the effects of 'third-hand' smoke. In the meantime, a concerted campaign against this consumer product with its deleterious effects of the health of the population is overdue.

Determinants of improved survival after oesophagectomy for cancer.

BACKGROUND: Survival after oesophagectomy for cancer seems to be improving. This study aimed to identify the most important contributors to this change. METHODS: Patients who underwent oesophagectomy from 1999 to 2010 were extracted from the Netherlands Cancer Registry. Four time periods were compared: 1999-2001 (period 1), 2002-2004 (period 2), 2005-2007 (period 3) and 2008-2010 (period 4). Hospital type, tumour location, tumour type, tumour differentiation, neoadjuvant therapy, operation type, (y)pT category, involvement of surgical resection margins, number of removed lymph nodes and number of involved lymph nodes were investigated in relation to trends in survival using multivariable analysis. RESULTS: A total of 4382 patients were identified. Two-year overall survival rates improved from 49·3 per cent in period 1 to 58·4, 56·2 and 61·0 per cent in periods 2, 3 and 4 respectively (P < 0·001). Multivariable survival analysis revealed that the improvement in survival between periods 3 and 4 was related to the introduction of neoadjuvant therapy. The improvement in survival between periods 1 and 2 could not be explained completely by the factors studied. The number of examined lymph nodes increased, especially between periods 2 and 3, but this increase was not associated with the improvement in survival. CONCLUSION: The observed increase in long-term survival after surgery for oesophageal cancer between 1999 and 2010 in the Netherlands is difficult to explain fully, although the recent increase seems to be partly attributable to the introduction of neoadjuvant therapy.

Comparison of extended hemicolectomy versus transverse colectomy in patients with cancer of the transverse colon.

BACKGROUND: Cancer of the transverse colon is rare and postoperative mortality tends to be high. Standard surgical treatment involves either extended hemicolectomy or transverse colectomy, depending on the location of the tumour. The aim of the present study was to compare postoperative mortality and five-year survival between these types of surgery. METHODS: For this observational study, data on patients with a tumour of the transverse colon, treated by open resection in the Dordrecht Hospital from 1989 through 2003, were derived from the database of the regional cancer registry. Information on type of resection, tumour stage, complications, postoperative mortality (30-day) and survival was abstracted from the medical files. Patients with multi-organ surgery, (sub)total colectomy or stage IV disease were excluded from the analysis, leaving a total series of 103 patients. RESULTS: Transverse colectomy comprised one third of operations, predominantly involving partial resections. Postoperative mortality was 6% (2/34) after transverse colectomy and 7% (5/69) after extended hemicolectomy. Five-year survival was slightly higher for the hemicolectomy group (61% versus 50%), but this difference did not reach statistical significance (p = 0.34). CONCLUSION: Our results confirm the high postoperative risk after surgery for cancer of the transverse colon and show that this risk does not depend on the type of surgery. Considering the satisfactory results after partial transverse colectomy, segmental resections may be considered as an option for the treatment of localised tumours of the transverse colon.

Comparison of 30-day, 90-day and in-hospital postoperative mortality for eight different cancer types.

BACKGROUND: Various definitions are used to calculate postoperative mortality. As variation hampers comparability between reports, a study was performed to evaluate the impact of using different definitions for several types of cancer surgery. METHODS: Population-based data for the period 1997-2008 were retrieved from the Rotterdam Cancer Registry for resectional surgery of oesophageal, gastric, colonic, rectal, breast, lung, renal and bladder cancer. Postoperative deaths were tabulated as 30-day, in-hospital or 90-day mortality. Postdischarge deaths were defined as those occurring after discharge from hospital but within 30 days. RESULTS: This study included 40,474 patients. Thirty-day mortality rates were highest after gastric (8·8 per cent) and colonic (6·0 per cent) surgery, and lowest after breast (0·2 per cent) and renal (2·0 per cent) procedures. For most tumour types, the difference between 30-day and in-hospital rates was less than 1 per cent. For bladder and oesophageal cancer, however, the in-hospital mortality rate was considerably higher at 5·1 per cent (+1·3 per cent) and 7·3 per cent (+2·8 per cent) respectively. For gastric, colonic and lung cancer, 1·0 per cent of patients died after discharge. For gastric, lung and bladder cancer, more than 3 per cent of patients died between discharge and 90 days. CONCLUSION: The 30-day definition is recommended as an international standard because it includes the great majority of surgery-related deaths and is not subject to discharge procedures. The 90-day definition, however, captures mortality from multiple causes; although this may be of less interest to surgeons, the data may be valuable when providing information to patients before surgery.

Re-resection rates after breast-conserving surgery as a performance indicator: introduction of a case-mix model to allow comparison between Dutch hospitals.

AIM: Re-resection rate after breast-conserving surgery (BCS) has been introduced as an indicator of quality of surgical treatment in international literature. The present study aims to develop a case-mix model for re-resection rates and to evaluate its performance in comparing results between hospitals. METHODS: Electronic records of eligible patients diagnosed with in-situ and invasive breast cancer in 2006 and 2007 were derived from 16 hospitals in the Rotterdam Cancer Registry (RCR) (n = 961). A model was built in which prognostic factors for re-resections after BCS were identified and expected re-resection rate could be assessed for hospitals based on their case mix. To illustrate the opportunities of monitoring re-resections over time, after risk adjustment for patient profile, a VLAD chart was drawn for patients in one hospital. RESULTS: In general three out of every ten women had re-surgery; in about 50% this meant an additive mastectomy. Independent prognostic factors of re-resection after multivariate analysis were histological type, sublocalisation, tumour size, lymph node involvement and multifocal disease. After correction for case mix, one hospital was performing significantly less re-resections compared to the reference hospital. On the other hand, two were performing significantly more re-resections than was expected based on their patient mix. CONCLUSIONS: Our population-based study confirms earlier reports that re-resection is frequently required after an initial breast-conserving operation. Case-mix models such as the one we constructed can be used to correct for variation between hospitals performances. VLAD charts are valuable tools to monitor quality of care within individual hospitals.

Causes of postoperative mortality after surgery for ovarian cancer.

Residual disease after cytoreductive surgery is an important prognostic factor in patients with advanced stage epithelial ovarian cancer (EOC). Aggressive surgical procedures necessary to achieve maximal cytoreduction are inevitably associated with postoperative morbidity and mortality. To determine causes of postoperative mortality (POM) after surgery for EOC all postoperative deaths in the southwestern part of the Netherlands over a 17-year period were identified and analysed by reviewing medical notes. Between 1989 and 2005, 2434 patients underwent cytoreductive surgery for EOC. Sixty-seven patients (3.1%) died within 30 days after surgery. Postoperative mortality increased with age from 1.5% (26/1765) for the age group 20-69 to 6.6% (32/486) for the age group 70-79 and 9.8% (18/183) for patients aged 80 years or older. Pulmonary failure (18%) and surgical site infection (15%) were the most common causes of death. Only a quarter of deaths resulted from surgical site complications. Our results suggest that causes of postoperative mortality after surgery for EOC are very heterogeneous. Given the impact of general complications, progress in preoperative risk assessment, preoperative preparation and postoperative care seem essential to reduce the occurrence of fatal complications.

Poor results after surgery for bronchioloalveolar carcinoma.

BACKGROUND: Bronchioloalveolar carcinoma (BAC) is suggested to be less aggressive than other types of lung cancer. To assess the option of treatment modification, actual outcome data were studied and compared with results for other types of lung cancer. METHOD: Retrospective analysis of all consecutive patients who underwent resection for stage I lung cancer in our hospital. For 18 BAC cases, histological specimens were re-evaluated and in three cases diagnosis was revised. RESULTS: In the period 1989 through 2000, 15 patients with BAC and 260 patients with other tumour types underwent surgery in our hospital. Five-year survival rates were 24 and 53%, respectively, (p = 0.01). CONCLUSIONS: Given the poor results after standard surgery, parenchyma-sparing operations do not seem justified in patients with invasive BAC.

Tumour size and vascular invasion predict distant metastasis in stage I breast cancer. Grade distinguishes early and late metastasis.

BACKGROUND: Recent Dutch guidelines recommend adjuvant systemic treatment (AST) for women with high grade stage I breast carcinoma > or =1 cm. High grade is defined as Bloom and Richardson grade 3 (B&R3), Nottingham modification, or mitotic activity (MAI) > or =10/1.59 mm2. AIMS: To investigate the validity of these histological prognostic factors as the exclusive defining criteria. MATERIALS/METHODS: Fifty patients with stage I breast carcinoma who developed distant metastases and 50 matched controls without metastasis were studied; none had received AST. RESULTS: Cases more often had tumours > or =1 cm (p = 0,019), B&R3 tumours (p = 0.059), grade 3 nuclei (p = 0.005), and vascular invasion (p = 0.007). No differences were found for MAI > or =10 (p = 0.46). In multivariate analysis, the only significant variables were vascular invasion and tumour size (odds ratios: 8.21 and 5.35, respectively). In a separate analysis, the 50 cases were divided into 25 patients with early and 25 with late metastasis. Those with early metastasis more often had B&R3 tumours (p = 0.009) and grade 3 nuclei (p = 0.006). No differences were found for tumours > or =1 cm, vessel invasion, or MAI > or =10. Using the present Dutch guidelines for AST, based on B&R3, 20 cases and 11 controls would have received AST. Based on MAI > or =10, 14 cases and 11 controls would have received AST. CONCLUSIONS: Tumour size and vessel invasion are the best prognostic factors for disease free survival in patients with stage I breast cancer. Dutch selection criteria for AST for these patients need to be improved. Some prognostic factors are time dependent, making their use as selection criteria for AST more complicated.

Survival differences between European and US patients with colorectal cancer: role of stage at diagnosis and surgery.

BACKGROUND: Population based colorectal cancer survival among patients diagnosed in 1985-89 was lower in Europe than in the USA (45% v 59% five year relative survival). AIMS: To explain this difference in survival using a new analytic approach for patients diagnosed between 1990 and 1991. SUBJECTS: A total of 2492 European and 11 191 US colorectal adenocarcinoma patients registered by 10 European and nine US cancer registries. METHODS: We obtained clinical information on disease stage, number of lymph nodes examined, and surgical treatment. We analysed three year relative survival, calculating relative excess risks of death (RERs, referent category US patients) adjusted for age, sex, site, surgery, stage, and number of nodes examined, using a new multivariable approach. RESULTS: We found that 85% of European patients and 92% of US patients underwent surgical resection. Three year relative survival was 69% for US patients and 57% for European patients. After adjustment for age, sex, and site, the RER was significantly high in all 10 European populations, ranging from 1.07 (95% confidence interval 0.86-1.32) (Modena, Italy) to 2.22 (1.79-2.76) (Thames, UK). After further adjustment for stage, surgical resection, and number of nodes examined (a determinant of stage), RERs ranged from 0.77 (0.62-0.96) to 1.59 (1.28-1.97). For some European registries the excess risk was small and not statistically significant. CONCLUSIONS: US-Europe survival differences in colorectal cancer are large but seem to be mostly attributable to differences in stage at diagnosis. There are wide variations in diagnostic and surgical practice between Europe and the USA.

Validation of the Charlson comorbidity index in patients with operated primary non-small cell lung cancer.

OBJECTIVE: To validate the influence of the Charlson comorbidity index (CCI) in patients with operated primary non-small cell lung cancer. METHODS: From January 1996 to December 2001, 205 consecutive resections for non-small cell lung cancer were performed at the Erasmus Medical Center Rotterdam. The patients ranged in age from 29 to 82 years, with a mean age of 64 years. In a retrospective study, each patient was scaled according to the CCI and the complications of surgery were determined. RESULTS: The hospital mortality was 2.4% (5/205). Of the 205 patients 167 (32.7%) experienced minor complications and 32 (15.6%) major complications. In univariate analysis, gender, grades 3-4 of the CCI, any prior tumor treated in the last 5 years and chronic pulmonary disease were significant predictors of adverse outcome. Multivariate analysis showed that only grades 3-4 of the CCI was predictive (odds ratio=9.8; 95% confidence interval=2.1-45.9). Although only comorbidity grades 3-4 was a significant predictor, for every increase of the comorbidity grade the relative risk of adverse outcome showed a slight increase. CONCLUSION: The CCI is strongly correlated with higher risk of surgery in primary non-small cell lung cancer patients and is a better predictor than individual risk factors.

Hospital volume and post-operative mortality after resection for gastric cancer.

AIMS: In low-volume hospitals, expertise in gastric surgery is difficult to maintain because of the decreasing incidence of gastric cancer and the fall of surgery for ulcer disease. We evaluated the prognostic impact of hospital volume on post-operative mortality (POM) in a consecutive series of 1978 patients. METHODS: Information on patients undergoing resection for gastric cancer in the period 1987-97 was retrieved from the Rotterdam Cancer Registry. The relationship between hospital volume and POM was analysed by logistic regression, adjusting for other prognostic factors. RESULTS: POM was 7.9% on average but varied between the 22 hospitals from 3.1% to 15.1% (P=0.15). Hospital volume had no prognostic influence (P=0.74). Prognostic factors were age (70-79 years odds ratio (OR)=3.8, 80+ years OR=6.0), sex (male OR=1.7), stage (IV OR=1.8) and (partial) gastrectomy for cardia cancers (OR=2.0). CONCLUSION: Variation in POM between hospitals was large but not related to hospital volume. For cardia cancer, POM rates were lower after oesophagogastrectomy.

High postoperative risk after pneumonectomy in elderly patients with right-sided lung cancer.

The present study investigated postoperative mortality (POM), its predictors and relationship with long-term survival in patients who underwent surgery for lung cancer. The 30-day mortality after thoracotomy in 1,830 patients from the Flemish multicentre hospital-based lung cancer registry was analysed according to patient, tumour, treatment and hospital characteristics and compared with 5-yr survival figures for the same patients. Overall POM was 4.4%. In univariate analysis age, extent of surgery and low hospital volume were associated with a higher POM. In multiple regression analysis age, extent of surgery and side of the pneumonectomy proved to be independent predictors of POM. In patients aged >70 yrs who underwent right-sided pneumonectomy POM was 17.8%. Overall, mortality was comparable to published series from referral centres. Age and extent of resection are the main predictors of postoperative mortality in lung-cancer patients. In the operable elderly patient, age alone does not justify denying the survival benefit experienced by resection of lung cancer. The high mortality after right-sided pneumonectomy in elderly patients warrants caution, as the treatment benefit may become marginal.