Nationwide Netherlands Cancer Registry Research Articles

Gender differences in tumor characteristics, treatment allocation and survival in stage I–III pancreatic cancer: a nationwide study

IntroductionSex and gender are modulators of health and disease and may have impact on treatment allocation and survival in patients with cancer. In this study, we analyzed the impact of sex and gender on treatment allocation and overall survival in patients with stage I-III pancreatic cancer. MethodsPatients with stage I-III pancreatic cancer diagnosed between 2015 and 2020 were selected from the nationwide Netherlands Cancer Registry. Associations between sex and gender and the probability of receiving surgical and/or systemic treatment were examined with multivariable logistic regression analyses. Overall survival was assessed with log rank test and multivariable Cox proportional hazard analysis. ResultsAmong 6855 patients, 51.2 % were female. Multivariable logistic regression analyses with adjustment for known confounders (age, performance status, comorbidities, tumor location, tumor stage and previous malignancies) showed that females less often received systemic chemotherapy compared to males (OR 0.799, 95 %CI 0.703–0.909, p < .001). No difference was found in the probability for undergoing surgical resection. Furthermore, females had worse overall survival compared to males (median OS 8.5 and 9.2 months respectively, 95 %CI 8.669–9.731). ConclusionThis nationwide study found that female patients with stage I-III pancreatic cancer significantly less often received systemic treatment and had worse overall survival as compared to males. Disparities in pancreatic cancer care can be decreased by recognizing and resolving potential obstacles or biases in treatment decision-making.

Abstract PO1-28-10: Tumor Infiltrating Lymphocytes identify patients with stage I TNBC with excellent outcome without chemotherapy

Abstract Introduction International guidelines recommend chemotherapy for most patients with stage I triple negative breast cancer (TNBC), except for special histological subtypes. However, the absolute benefit of systemic treatment for all stage I TNBC patients is not well known and no tools are yet available to select patients with an excellent prognosis for whom the chemotherapy can be safely omitted. High levels of stromal tumor infiltrating lymphocytes (sTILs) are strongly associated with favorable prognosis in TNBC, however, data solely focusing on patients with stage I TNBC who did not receive chemotherapy are lacking. Methods Patients with pT1N0M0 TNBC diagnosed between 2005 and 2015 not treated with (neo)adjuvant chemotherapy were identified from the nationwide Netherlands Cancer Registry (NCR) and linked to the national pathology database (PALGA). Newly sectioned hematoxylin &amp; eosin (H&amp;E) slides were used for central review of the histology and sTILs scoring following the International TIL working group guidelines (www.tilsinbreastcancer.org). Cause of death was provided by Statistics Netherlands (CBS). Primary endpoint was breast-cancer specific survival (BCSS) at 5-, 10- and 15-years for prespecified sTILs cut-offs of 30%, 50% and 75% sTILs. Results sTILs were evaluated for 1,041 patients with stage I TNBC who did not receive (neo)adjuvant chemotherapy. Mean age at diagnosis was 64.4 years [range 26 – 96] and median sTILs value was 5%. Most tumors (91.5%) were invasive ductal adenocarcinomas of no special type (NST) and 6.6% were of histological special types. In 52% of the patients the tumor was &amp;gt;1cm (pT1cN0). Median follow-up was 9.4 years in which 335 patients had died, of whom 107 due to breast cancer. Patients with pT1abN0 tumors had a favorable prognosis compared with patients with a pT1cN0 tumor (HR 0.47, CI 0.32- 0.72). 10-year BCSS in patients with pT1ab was 91.8% and 85.8% in patients with pT1c tumors. In the overall cohort, sTILs-levels of at least 30% were associated with better BCSS compared to sTILs &amp;lt; 30% (HR 0.45, CI 0.26 – 0.77), with 10year-BCSS of 96% and 87%, respectively (table 1). Patients with TNBC of special histological subtype had low sTILs (median 1%). A univariate cox model showed no association between sTILs (continuous) and BCSS in TNBC of special histological subtype (p = 0.56). Next, the prognostic value of sTILs was evaluated separately for pT1ab and pT1c. High sTILs ≥50% were not associated with improved BCSS compared to low sTILs &amp;lt; 50% in patients with pT1ab (HR 1.35, CI 0.65 – 2.82, p = 0.42). In contrast, high sTILs ≥50% showed a strong prognostic importance over low sTILs &amp;lt; 50% (HR 0.27, CI 0.10 – 0.74) in patients with pT1C tumors. We found excellent 10year-BCSS of 95% for patients if sTILs ≥50%, which further increases to 98% with sTILs ≥75% contrasting 10year-BCSS of 83% for patients with sTILs &amp;lt; 30%. Conclusions sTILs-levels provide important prognostic information in patients with stage I TNBC who did not receive (neo)adjuvant chemotherapy. The outcome of patients with pT1c TNBC and sTILs ≥50% was excellent, with 10year-BCSS of 95%, and 98% if sTILs &amp;gt;75%. This large registry study provides a foundation for clinical trials in patients with stage I TNBC with high TILs to prospectively confirm their excellent survival without chemotherapy. Citation Format: Veerle Geurts, Sara Balduzzi, Hugo Horlings, Tessa G Steenbruggen, Sabine Siesling, Sylvia Adams, Gabe Sonke, Roberto Salgado, Marleen Kok. Tumor Infiltrating Lymphocytes identify patients with stage I TNBC with excellent outcome without chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-28-10.

The effect of definitive chemoradiotherapy on quality of life in patients with esophageal cancer: Analysis of the Dutch population-based POCOP registry.

323 Background: Definitive chemoradiotherapy (dCRT) can achieve durable local control and even curation in patients with locally advanced irresectable esophageal carcinoma. However, due to side-effects of this treatment, survival benefit may come at the cost of quality of life (QoL). This study aims to report prospectively collected patient-reported outcome measures (PROMs) after dCRT. Methods: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus receiving dCRT and participating in the Prospective Observational Cohort Study of Oesophageal-gastric cancer Patients (POCOP) were eligible. dCRT was defined as radiotherapy consisting of at least 50.4Gy/28F with concomitant weekly carboplatin and paclitaxel. PROMs were extracted from the POCOP database, which uses validated questionnaires EORTC QLQ-C30 and OG25. Questionnaires were collected at baseline, at three months (3M), at six months (6M) and every three months thereafter for a total follow-up of 2 years. Clinical data were derived from the nationwide Netherlands Cancer Registry (NCR). PROMs were compared to baseline values using mixed effect models. Results: In total, 153 patients were included. The median age was 70 years and patients were predominantly male (73.2%). 51% of patients had esophageal adenocarcinoma and the majority had a performance status score 0 (39.9%) or 1 (46.4%). The number of returned questionnaires ranged from 96 at baseline to 106 at 3M and 36 at 2 years. Global Health Status at baseline was 69.9 (SD 17.6) and declined at 3M, although not significantly. At later time points, scores showed a trend towards improvement compared to baseline. Patients reported significantly lower physical (71.5, SD 19.4), role (67.8, SD 31.0) and social functioning (72.4, SD 29.1) at 3M compared to baseline (82.7, 79.7 and 81.5 respectively, all p&lt;0.01). For social and role functioning, scores returned to baseline at 6M and subsequent time points, but physical functioning scores remained significantly lower compared to baseline. Patients reported more fatigue at 3M (42.0, SD 27.1) compared to baseline (28.9, p&lt;0.001) but recovered at 6M. Emotional functioning significantly improved from baseline (73.5, SD 19.7) to 3M (80.1, SD 21.7, p=0.002) and subsequent time points. Patients reported an improvement of several disease-specific symptoms such as eating restrictions (-20.3, p&lt;0.001), weight loss (-12.7, p&lt;0.01), odynophagia (-21.9, p&lt;0.001) and dysphagia (-17.9, p&lt;0.001) at all time points, but most pronounced at 18 months after baseline. Conclusions: Prospectively collected PROMs showed that fatigue, social and role functioning temporarily deteriorated after dCRT. Physical functioning was decreased after three months and did not recover to baseline. Emotional functioning significantly improved and the burden of disease-specific symptoms decreased.

Beyond Median Overall Survival: Estimating Trends for Multiple Survival Scenarios in Patients With Metastatic Esophagogastric Cancer.

In recent years, clinical trials have shown improved survival of patients with metastatic esophageal or gastric cancer. The number of patients participating in clinical trials is limited, and survival improvements observed from clinical trials are unrepresentative for the full population. The aim of our study was to assess trends in survival for the best-case, typical, and worst-case scenarios in patients with metastatic esophageal or gastric cancer. We selected patients with metastatic esophageal or gastric cancer diagnosed between 2006 and 2020 from the nationwide Netherlands Cancer Registry. Survival was calculated for different percentiles of the survival curve for each incidence year (eg, the 10th percentile [p10] represents the top 10% of patients with the best survival): p10 (best-case), p25 (upper-typical), p50 (median), p75 (lower-typical), and p90 (worst-case). Weighted linear regression analyses were performed to test whether changes in survival were significant. The overall median survival between 2006 and 2020 remained unchanged for patients with esophageal cancer (n=10,448; from 5.2 to 5.2 months, respectively; P=.06) and improved for patients with gastric cancer (n=10,512; from 3.5 to 4.3 months, respectively; P=.001). For patients with esophageal cancer, survival for the best-case scenario (p10; best 10% of patients) significantly improved from 17.2 to 21.0 months (P=.006). For patients with gastric cancer, survival significantly improved for the best-case scenario (p10) from 15.9 to 23.5 months (P<.001) and the upper-typical scenario (p25) scenario improved from 7.9 to 9.9 months (P<.001). Despite significant survival improvements in clinical trials, survival improvements were not observed for the majority of patients treated in daily clinical practice. An increase in survival was only observed for patients with the best prognosis.

Therapies and Outcomes for Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Contemporary, Nationwide, Population-Based Study in the Netherlands

Background Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a dismal prognosis. Encouragingly, the treatment landscape of R/R DLBCL is rapidly evolving with treatments such as CAR T-cell therapy and bispecific antibodies that significantly improve the prognosis for particular patient subsets. The SCHOLAR-1 study, the first to provide a benchmark for future clinical trials in R/R DLBCL, described outcomes in R/R DLBCL patients based on data from 2 large randomized trials and 2 academic databases. Since SCHOLAR-1 is not population-based, any extrapolation of the study results to a daily practice population requires caution. Currently, population-based studies confirming findings from SCHOLAR-1 are lacking. Therefore, our nationwide, population-based study aimed to validate the results of SCHOLAR-1 in patients with DLBCL in contemporary clinical practice. Methods We selected all adult DLBCL patients, including transformed follicular lymphoma (tFL) and primary mediastinal B-cell lymphoma (PMBCL), diagnosed between 2014-2016 in the Netherlands from the nationwide Netherlands Cancer Registry (NCR). Data on treatment and survival were available in the NCR with follow-up until December 31, 2021. Inclusion criteria similar to SCHOLAR-1 were used: (i) diagnosis of DLBCL, tFL, or PMBCL, (ii) treatment with an anti-CD20 monoclonal antibody and an anthracycline in first-line, (iii) refractory disease defined as stable disease or progressive disease as the best response to therapy or relapse ≤12 months after autologous stem cell transplantation (ASCT), (iv) and initiation of subsequent treatment at the first instance of refractory disease. Patients were divided into 3 subgroups (i.e., primary refractory, refractory to ≥ second-line treatment, and relapsed ≤12 months post-ASCT) based on the first instance of refractory disease. Descriptive statistics and the Kaplan-Meier method were used to analyze baseline characteristics and overall survival (OS), respectively, after the start of treatment for the first instance of refractory disease. OS was measured until death or the end of follow-up (December 31, 2021). Results Between 2014-2016, 4,085 adult DLBCL patients were diagnosed in the Netherlands, of whom 275 (7%) met the above described criteria (i, ii and iii) for R/R DLBCL. Of these 275 patients, 122 (44%) received subsequent treatment for the first instance of refractory disease. These 122 patients were included in our analytical cohort (61% male, median age: 63 years (IQR: 51-69), 70% Ann Arbor stage III-IV) and mainly comprised DLBCL (87%), followed by tFL (9%) and PMBCL (4%). Forty-six percent had primary refractory disease, 36% was refractory to ≥ second-line treatment and 18% relapsed ≤12 months post-ASCT. The best response to subsequent treatment was assessed for 86 patients, with an overall response rate and complete remission rate of 23% (N=20) and 14% (N=12), respectively. The median OS from the start of subsequent treatment was 3.5 months (95% confidence interval [CI], 2.5-4.3 months), with a 2-year OS rate of 11% (95% CI, 6-17%) (Figure 1A). More specifically, the median OS across the 3 refractory disease subgroups was 3.2 (95% CI, 1.8-4.2 months), 2.5 (95% CI, 1.7-4.3 months), and 9.2 months (95% CI, 3.0-13.9 months), respectively. The corresponding 2-year OS rates were 13% (95% CI, 5-23%), 2% (95% CI, 0.2-10%), and 23% (95% CI, 8-41%), respectively (Figure 1B). Conclusions To contextualize results for R/R DLBCL patients in daily practice, population-based studies are vital to validate results derived from clinical trials or academic databases. Remarkably, more than 50% of the 275 patients meeting refractory disease criteria in our cohort had to be excluded, as they did not receive subsequent treatment at the first instance of refractory disease. Also, compared to SCHOLAR-1, patients with refractory disease in our study had an even lower median OS of 3.5 months (95% CI, 2.5-4.3 months) vs. 6.3 months (95% CI, 5.9-7.0 months) and a lower 2-year OS rate of 11% (95% CI, 6-17%) vs. 20% (95% CI, 16-23%). Our results emphasize the need to improve the dismal prognosis of patients with R/R DLBCL. The real-world data in this study support future research (e.g., benchmarking) and facilitate comparison of (cost-)effectiveness of novel treatments with usual care for patients with DLBCL in clinical practice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of metachronous contralateral breast cancer in patients with primary invasive lobular breast cancer: Results from a nationwide cohort.

Lobular primary breast cancer (PBC) histology has been proposed as a risk factor for contralateral breast cancer (CBC), but results have been inconsistent. We investigated CBC risk and the impact of systemic therapy in lobular versus ductal PBC. Further, CBC characteristics following these histologic subtypes were explored. We selected 74,373 women diagnosed between 2003 and 2010 with stage I-III invasive PBC from the nationwide Netherlands Cancer Registry. We assessed absolute risk of CBC taking into account competing risks among those with lobular (n= 8903), lobular mixed with other types (n= 3512), versus ductal (n= 62,230) histology. Hazard ratios (HR) for CBC were estimated in a cause-specific Cox model, adjusting for age at PBC diagnosis, radiotherapy, chemotherapy and/or endocrine therapy. Multivariable HRs for CBC were 1.18 (95% CI: 1.04-1.33) for lobular and 1.37 (95% CI: 1.16-1.63) for lobular mixed versus ductal PBC. Ten-year cumulative CBC incidences in patients with lobular, lobular mixed versus ductal PBC were 3.2%, 3.6% versus 2.8% when treated with systemic therapy and 6.6%, 7.7% versus 5.6% in patients without systemic therapy, respectively. Metachronous CBCs were diagnosed in a less favourable stage in 19%, 26% and 23% and less favourable differentiation grade in 22%, 33% and 27% than the PBCs of patients with lobular, lobular mixed and ductal PBC, respectively. In conclusion, lobular and lobular mixed PBC histology are associated with modestly increased CBC risk. Personalised CBC risk assessment needs to consider PBC histology, including systemic treatment administration. The impact on prognosis of CBCs with unfavourable characteristics warrants further evaluation.

First- and Second-Line Palliative Systemic Treatment Outcomes in a Real-World Metastatic Pancreatic Cancer Cohort.

Metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor survival rate, which can be improved by systemic treatment. Consensus on the most optimal first- and second-line palliative systemic treatment is lacking. The aim of this study was to describe the use of first- and second-line systemic treatment, overall survival (OS), and time to failure (TTF) of first- and second-line treatment in metastatic PDAC in a real-world setting. Patients with synchronous metastatic PDAC diagnosed between 2015 and 2018 who received systemic treatment were selected from the nationwide Netherlands Cancer Registry. OS and TTF were evaluated using Kaplan-Meier curves with log-rank test and multivariable Cox proportional hazard analyses. The majority of 1,586 included patients received FOLFIRINOX (65%), followed by gemcitabine (18%), and gemcitabine + nab-paclitaxel (13%) in the first line. Median OS for first-line FOLFIRINOX, gemcitabine + nab-paclitaxel, and gemcitabine monotherapy was 6.6, 4.7, and 2.9 months, respectively. Compared to FOLFIRINOX, gemcitabine + nab-paclitaxel showed significantly inferior OS after adjustment for confounders (hazard ratio [HR], 1.20; 95% CI, 1.02-1.41), and gemcitabine monotherapy was independently associated with a shorter OS and TTF (HR, 1.98; 95% CI, 1.71-2.30 and HR, 2.31; 95% CI, 1.88-2.83, respectively). Of the 121 patients who received second-line systemic treatment, 33% received gemcitabine + nab-paclitaxel, followed by gemcitabine (31%) and FOLFIRINOX (10%). Based on population-based data in patients with metastatic PDAC, treatment predominantly consists of FOLFIRINOX in the first line and gemcitabine with or without nab-paclitaxel in the second line. FOLFIRINOX in the first line shows superior OS compared with gemcitabine with or without nab-paclitaxel.

Association of histological features with laryngeal squamous cell carcinoma recurrences: a population-based study of 1502 patients in the Netherlands

BackgroundRecurrences remain an important problem in laryngeal squamous cell carcinoma. Little has been described about histological characteristics of the primary laryngeal tumor that may be associated with recurrences. Identifying risk factors for recurrences might help in adapting treatment or follow-up. Using real-life population-based data, we aimed to identify histological features of the primary tumor associated with recurrences and overall survival.Material and methodsDemographic, clinical and treatment information on all first primary invasive laryngeal tumors diagnosed in 2010–2014 (N = 3705) were extracted from the population-based nationwide Netherlands cancer registry (NCR) and linked to PALGA, the nationwide Dutch pathology registry, to obtain data on histological factors and recurrences. For a random 1502 patients histological information i.e., keratinization, perineural invasion (PNI+), vascular invasion (VI+), growth pattern, degree of differentiation, extracapsular spread (ECS+), cartilage- and bone invasion and extralaryngeal extension, was manually extracted from narrative pathology reports and analyzed for locoregional recurrence and overall survival using cox regression analysis.ResultsIn total, 299 patients developed a locoregional recurrence and 555 patients died. Keratinization (HR = 0.96 (95%CI: 0.68–1.34) p = 0.79), two or three adverse characteristics (PNI+, VI+, non-cohesive growth) (HR = 1.38 (95% CI: 0.63–3.01) p = 0.42), and ECS+ (HR = 1.38 (95% CI: 0.48–4.02) p = 0.55) were not associated to recurrence. For death, also no significant association was found.ConclusionIn this population-based real-life dataset on laryngeal carcinoma in the Netherlands, histological factors were not associated with locoregional recurrences or overall survival, but future studies should investigate the role of these features in treatment decisions.

Prevalence of KRAS p.(G12C) in stage IV NSCLC patients in the Netherlands; a nation-wide retrospective cohort study

ObjectivesThe recent accelerated FDA approval of sotorasib, a highly selective KRAS G12C inhibitor, offers new opportunities for the treatment of KRAS p.(G12C)-mutated non-squamous non-small cell lung cancer (NSCLC). The objective of the current study was to the determine the prevalence of KRAS mutations in stage IV non-squamous NSCLC in The Netherlands to reveal the potential impact of upcoming KRAS targeted therapy. Materials and methodsAll patients diagnosed with stage IV non-squamous NSCLC in 2013, 2015 and 2017 in the Netherlands were selected by linking the nation-wide Netherlands Cancer Registry (NCR) and the Dutch Pathology Registry (PALGA). Demographic and pathological variables were retrieved from the pathology reports including sex, age, KRAS mutation status, molecular test method used, and the mutation status of other genes. ResultsPrevalence for any KRAS mutations in codon 12/13/61/146 was 39.1%. KRAS p.(G12C) was detected in 15.5% of all non-squamous NSCLC cases representing 39.6% of all KRAS-mutant cases. National testing rate for KRAS mutations increased from 70% in 2013 to 82% in 2017. Testing techniques changed significantly over time with next generation sequencing as the main used method in 2017 (71.6%) but did not affect prevalence of KRAS mutations over time. When KRAS was tested as part of a larger panel, the KRAS p.(G12C) mutation was frequently reported with a concurrent mutation in TP53 (47.7%) or STK11 (10.3%). ConclusionThe high prevalence for KRAS p.(G12C) offers a promising new specific treatment option for 15% of all stage IV non-squamous NSCLC patients.

Age-specific incidence, treatment, and survival trends in esophageal cancer: a Dutch population-based cohort study

Background Data on the age-specific incidence of esophageal cancer are lacking. Our aim was to investigate the age-stratified incidence, treatment, and survival trends of esophageal cancer in the Netherlands, with a focus on adults <50 years. Material and methods Patients diagnosed with esophageal cancer were included from the nationwide Netherlands Cancer Registry (1989–2018). Follow-up data were available until 31 December 2018. Annual percentage changes of incidence were analyzed according to age group (<50, 50–74, and ≥75 years) and histology type: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). Treatment trends and relative survival rates (RSR) were estimated by age and stage grouping. Results A total 59,584 patients were included. In adults <50 years, EAC incidence tripled (mean increase per year: males 1.5%, females 3%), while the incidence of ESCC decreased (mean decrease per year: males −5.3%, females −4.3%). Patients <50 years more often presented with advanced disease stages compared to older patients and were more likely to receive multimodality treatments. Most patients <50 years with potentially curable disease were treated with neoadjuvant chemoradiotherapy followed by surgery compared to patients 50–74 and ≥75 years (74% vs. 55% vs. 15%, respectively; p < .001), and received more frequent systemic therapy once staged with palliative disease (72% vs. 54% vs. 19%, respectively; p < .001). The largest RSR improvement was seen in patients <50 years with early-stage (five years: +47%), potentially curable (five years: +22%), and palliative disease (one year: +11%). Over time, a trend of increasing survival difference was seen between patients <50 and ≥75 years with potentially curable (five-year difference: 17% to 27%) and palliative disease (one-year difference: 11% to 20%). Conclusion The incidence of EAC is increasing in adults <50 years in the Netherlands. Differences in the use of multimodality treatments with curative or life-prolonging intent in different age categories may account for increasing survival gaps.

Pomalidomide in Patients With Relapsed and/or Refractory Multiple Myeloma: A Prospective Study Within the Nationwide Netherlands Cancer Registry.

Patients with relapsed and/or refractory multiple myeloma (RRMM) generally have limited treatment options and a poor prognosis. Previous trials demonstrated that pomalidomide combined with low-dose dexamethasone (Pd) is effective in these patients with significant responses and improved progression-free survival (PFS). Pd has been approved in RRMM patients who received ≥2 prior lines of therapy. Here, we present the results of a population-based study of patients with RRMM treated with Pd in The Netherlands from time of pomalidomide approval. Using the nationwide Netherlands Cancer Registry, data from all nontrial patients with RRMM treated with Pd were collected. Data were analyzed of response, PFS, and overall survival (OS). A total of 237 patients were included in this analysis. Previous treatment consisted of a proteasome inhibitor in 227 patients (96%) and/or an immune-modulating agent in 235 patients (99%). One hundred forty patients (59%) were refractory to an immune-modulating agent in their last line of therapy. Median time from diagnosis to treatment with Pd was 4.9 years (interquartile range, 2.7–7.9), and the median number of prior treatments was 4 (interquartile range, 3–5). Median PFS and OS for all patients were 3.6 months (95% confidence interval [CI], 3.1–3.8) and 7.7 months (95% CI, 5.7–9.7), respectively. For patients achieving ≥PR, median PFS and OS were 10.6 months (95% CI, 8.3–12.9) and 16.3 months (95% CI, 13.6–23.2), respectively. This nationwide, population-based registry study confirms data shown in pivotal clinical trials on Pd. PFS in this analysis is comparable to PFS observed in those clinical trials.

Primary therapy and relative survival in patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia: a population-based study in the Netherlands, 1989-2018.

SummaryIt is unclear how treatment advances impacted the population‐level survival of patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (LPL/WM). Therefore, we assessed trends in first‐line therapy and relative survival (RS) among patients with LPL/WM diagnosed in the Netherlands between 1989 and 2018 (N = 6232; median age, 70 years; 61% males) using data from the nationwide Netherlands Cancer Registry. Patients were grouped into three age groups (<65, 66–75 and >75 years) and four calendar periods. Overall, treatment with anti‐neoplastic agents within 1 year post‐diagnosis gradually decreased over time, following a broader application of an initial watch‐and‐wait approach. Approximately 40% of patients received anti‐neoplastic therapy during 2011–2018. Furthermore, use of chemotherapy alone decreased over time, following an increased application of chemoimmunotherapy. Detailed data among 1596 patients diagnosed during 2014–2018 revealed that dexamethasone‐rituximab‐cyclophosphamide was the most frequently applied regimen; its use increased from 14% to 39% between 2014 and 2018. The 5‐year RS increased significantly over time, particularly since the introduction of rituximab in the early–mid 2000s. The 5‐year RS during 1989–1995 was 75%, 65%, and 46% across the age groups compared to 93%, 85%, and 79% during 2011–2018. However, the survival improvement was less pronounced after 2011. Collectively, the impressive survival improvement may be accounted for by broader application of rituximab‐containing therapy. The lack of survival improvement in the post‐rituximab era warrants studies across multiple lines of therapy to further improve survival in LPL/WM.

Occult lymph node metastases in patients without residual muscle-invasive bladder cancer at radical cystectomy with or without neoadjuvant chemotherapy: a nationwide study of 5417 patients

PurposeLittle is known about the prevalence of occult lymph node metastases (LNM) in muscle-invasive bladder cancer (MIBC) patients with pathological downstaging of the primary tumor. We aimed to estimate the prevalence of occult LNM in patients without residual MIBC at radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) or neoadjuvant radiotherapy (NAR), and to assess overall survival (OS).MethodsPatients with cT2-T4aN0M0 urothelial MIBC who underwent RC plus pelvic lymph node dissection (PLND) with curative intent between January 1995–December 2013 (retrospective Netherlands Cancer Registry (NCR) cohort) and November 2017–October 2019 (prospective NCR-BlaZIB cohort (acronym in Dutch: BlaaskankerZorg In Beeld; in English: Insight into bladder cancer care)) were identified from the nationwide NCR. The prevalence of occult LNM was calculated and OS of patients with <(y)pT2N0 vs. <(y)pT2N+ disease was estimated by the Kaplan–Meier method.ResultsIn total, 4657 patients from the NCR cohort and 760 patients from the NCR-BlaZIB cohort were included. Of 1374 patients downstaged to <(y)pT2, 4.3% (N = 59) had occult LNM 4.1% (N = 49) of patients with cT2-disease and 5.6% (N = 10) with cT3-4a-disease. This was 4.0% (N = 44) in patients without NAC or NAR, 4.5% (N = 10) in patients with NAC, and 13.5% (N = 5) in patients with NAR but number of patients treated with NAR and downstaged disease was small. The prevalence of <(y)pT2N+ disease was 4.2% (N = 48) in the NCR cohort and 4.6% (N = 11) in the NCR-BlaZIB cohort. For patients with <(y)pT2N+ and <(y)pT2N0, median OS was 3.5 years (95% CI 2.5–8.9) versus 12.9 years (95% CI 11.7–14.0), respectively.ConclusionOccult LNM were found in 4.3% of patients with cT2-4aN0M0 MIBC with (near-) complete downstaging of the primary tumor following RC plus PLND. This was regardless of NAC or clinical T-stage. Patients with occult LNM showed considerable worse survival. These results can help in counseling patients for bladder-sparing treatments.

The fear of cancer progression and recurrence in patients with pancreatic cancer.

4132 Background: Patients with pancreatic cancer run a considerable risk of disease progression or, after resection, disease recurrence, ultimately leading to death. Therefore, it is plausible that pancreatic cancer patients experience fear of cancer recurrence or progression (FOP). The aim of this study was to compare FOP in patients with pancreatic cancer treated with surgery, palliative systemic treatment or best supportive care (BSC), and examine the association between quality of life (QoL) and FOP and between FOP and overall survival (OS), respectively. Methods: This prospective multicenter cohort study included patients diagnosed with pancreatic cancer between 2015 and 2018, who participated in the Dutch Pancreatic Cancer Project (PACAP). Data on FOP (worry of cancer progression scale [WOPS]) and QoL (EORTC QLQ-C30 summary scale score), were obtained from the PACAP database. Data regarding patient and tumor characteristics were derived from the nationwide Netherlands Cancer Registry. The association between QoL and WOPS was assessed with logistic regression analysis. OS was evaluated using Kaplan Meier curves with log-rank test and multivariable Cox proportional hazard analyses. Results: In total, 315 patients were included, of whom 111 patients underwent surgery, 138 received palliative systemic treatment, and 66 BSC. WOPS scores tended to decrease and stabilize over time in all subgroups. Patients who underwent surgery had significantly lower WOPS scores (i.e. less FOP) at initial diagnosis compared to patients in the palliative systemic treatment and BSC group (p = 0.004). Higher QoL scores were independently associated with a lower probability of high WOPS scores in patients receiving BSC only (OR 0.95, P = 0.006). Baseline WOPS score was not independently associated with OS. Conclusions: Pancreatic cancer patients reported FOP at diagnosis, which decreased and stabilized over time. Given the distress that FOP evokes, FOP should be explicitly addressed by health care providers when guiding pancreatic cancer patients through their treatment trajectory, especially those receiving palliative treatment or BSC.

Abstract PS10-07: Pathologic complete response and 3-year survival with or without pertuzumab using real-world data of stage II and III HER2-positive breast cancer

Abstract Background Pertuzumab greatly improves pathologic complete response (pCR) rates in early stage HER2-positive breast cancer. Long-term benefit of pertuzumab, however, is less well established, as follow-up of the NEOSPHERE and APHINITY trials did not show clear improvement in overall survival, although patients with high risk of recurrence (e.g. node positive) appeared to benefit. Since its long-term benefit remains uncertain, we compared outcome of patients treated with or without pertuzumab in a quasi-random experiment using real-world data. Methods We identified all patients with stage II-III HER2-positive breast cancer in the Netherlands treated with neoadjuvant trastuzumab containing chemotherapy between November 2013 and January 2016 from the nationwide Netherlands Cancer Registry. During this period, reimbursement of pertuzumab in the Netherlands was pending and pertuzumab was only available as trial medication for patients in 37 hospitals that participated in the TRAIN-2 study. This setting created a unique opportunity to compare two quasi-random cohorts of patients treated with or without pertuzumab. We used logistic regression analysis to evaluate the association between pertuzumab use and pCR (ypT0/is, ypN0) and Kaplan-Meier estimates and Cox regression analysis for the association with overall survival (OS). Multivariate analyses included age, cT-status, cN-status, hormone receptor (HR) status and grade. Multiple imputation was used to impute missing data for multivariate analysis. Results We identified 1,124 eligible patients of whom 453 (40%) had received pertuzumab. Baseline characteristics were comparable with and without pertuzumab: 61% of tumors were cT2, 22% cT3, 66% were node positive and 62% ER and/or PR-positive. Grade was missing for 17% in patients treated with and 46% in patients treated without pertuzumab and therefor imputed. PCR in breast and axilla could be determined in 1,091 patients. Pertuzumab use improved pCR rates (65% vs 41%, adjusted odds ratio [aOR] 3.01; 95% confidence interval [CI] 2.29-3.97; p&amp;lt;0.001). At a median follow-up of 59 months (IQR 53-66) 23 deaths had occurred in the pertuzumab group and 68 in the non-pertuzumab group (3-year OS 98% vs 95%; adjusted hazard ratio [aHR]: 0.61; 95% CI:0.38-1.00, p=0.048). Pertuzumab benefit appeared largest in ER/PR negative and cN+ tumors, although the number of events in each subgroup was too small for formal comparisons. Complete-case analysis showed similar aHRs, but with broader 95% confident intervals. Conclusion This real-world quasi-experiment confirms the efficacy of pertuzumab to achieve a pCR in stage II and III HER2-positive breast cancer. In addition, these data suggest a small absolute overall survival benefit with pertuzumab, most prominently in hormone receptor negative and node positive tumors. Despite the unique setting of two quasi-random cohorts treated with or without pertuzumab and very similar baseline characteristics, residual confounding cannot be fully excluded. Breast cancer specific evaluation and translational work including central revision of tumor grade for missing cases is pending. pCR (%)3-yr OS (%)Ptzno PtzPtzno PtzaHR (95%CI)Overall65%41%98%95%0.61 (0.38-1.00)HR-positive51%32%98%97%0.70 (0.36-1.33)HR-negative86%55%97%92%0.54 (0.26-1.13)cN071%46%99%100%0.54 (0.14-2.00)cN+62%38%97%93%0.65 (0.39-1.09) Citation Format: Anna van der Voort, Marte Liefaard, Mette van Ramshorst, Erik van Werkhoven, Astrid Scholten, Jelle Wesseling, Marie-Jeanne Vrancken Peeters, Linda de Munck, Gabe Sonke. Pathologic complete response and 3-year survival with or without pertuzumab using real-world data of stage II and III HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-07.

Disease-free and overall survival in nonmetastatic esophageal or gastroesophageal junctional cancer after treatment with curative intent: A nationwide population-based study.

246 Background: Among patients with potentially curable esophageal cancer (EC) or gastroesophageal junctional cancer (GEJC) treated with curative intent, survival remains poor and around half of these patients have disease recurrence within a few years. This study addresses the need for real-world data on disease-free survival (DFS) and overall survival (OS) in patients with EC or GEJC who underwent potentially curative treatment. Methods: Patients selected from the nationwide Netherlands cancer registry (NCR) had received a primary diagnosis of non-metastatic EC or GEJC (excluding patients with T4b tumors) in 2015 or 2016 and received treatment with curative intent. Curative intent was defined as receiving resection (with or without [neo]adjuvant therapy) or definitive chemoradiotherapy (dCRT) without surgery. DFS and OS were analysed using Kaplan-Meier curves with Log-Rank test from resection date or end of dCRT. A sub-analysis was performed for NCR patients selected to align with the population of the CheckMate-577 phase 3 study of adjuvant nivolumab, i.e. patients with non-cervical stage II/III disease, R0 resection and residual pathological disease after neoadjuvant CRT (nCRT) and surgery. Results: We identified 1916 patients of median age of 67 years and predominantly male (76%). The majority (79%) received surgery and 21% of patients received dCRT. In resected patients, 83% received nCRT, 10% neoadjuvant chemotherapy (with or without adjuvant CRT) and 7% received no (neo)adjuvant treatment. Compared to the resected group, the population receiving dCRT had significantly fewer males (65% vs 78%), a higher median age (72 vs 65 years) and worse performance status. Patients receiving dCRT significantly shorter median DFS (14.2 months) and OS (20.9 months) compared to resected patients (DFS: 26.4 months, p &lt; 0.001; OS: 40.5 months, p &lt; 0.001). The 1- and 3-year DFS probabilities were 68% and 44%, respectively, in resected patients, and 56% and 24%, respectively, in patients receiving dCRT. In patients receiving nCRT followed by surgery, the median DFS and OS were 25.2 and 38.0 months, respectively, and 1- and 3-year DFS probabilities were 67% and 43%, respectively. In the sub-analysis (n = 725) the median DFS and OS were 19.2 and 29.4 months, respectively, and the 1- and 3-year DFS rates were 62% and 36%, respectively. Conclusions: Although patients are treated with curative intent, a considerable amount of patients with non-metastatic EC or GEJC experienced recurrence within two years. Resected patients had a higher DFS and OS compared to patients receiving dCRT.

Treatment patterns and overall survival for recurrent esophageal or gastroesophageal junctional cancer: A nationwide European population-based study.

186 Background: Esophageal cancer has a high risk for recurrence after treatment with curative intent. This study describes the characteristics of patients with esophageal or gastroesophageal junctional cancer at the time of recurrence, treatment patterns and overall survival (OS) after recurrence. Methods: Patients selected from the nationwide Netherlands cancer registry had received a primary diagnosis of non-metastatic squamous cell carcinoma or adenocarcinoma of esophagus or gastroesophageal junction in 2015 or 2016 and experienced recurrence after primary treatment with curative intent. Curative intent was defined as receiving resection (with or without [neo]adjuvant therapy) or definitive chemoradiotherapy (dCRT) without surgery. Recurrence within or after six months was calculated from resection date or end of dCRT. OS was calculated from recurrence and analysed using Kaplan-Meier curves with Log-Rank test. Results: We identified 856 patients who presented with disease recurrence after potentially curative treatment with resection (75%) or dCRT (25%). At recurrence, the majority of patients were male (78%),the median age was 68 years and 77% of patients had adenocarcinoma. Twenty-six percent of patients had disease recurrence within six months after curative treatment. Eighteen percent of patients had locoregional recurrence only, 48% distant recurrence only and 33% both locoregional and distant recurrence. Among patients with a distant recurrence, 37% had metastases in non-regional lymph nodes, 31% in the liver and 30% in the lung. After disease recurrence, 29% of patients received systemic therapy (chemo- or targeted therapy), 5% chemoradiotherapy, 1% surgery and 66% best supportive care only. The most common systemic treatment regimen was CapOx/FOLFOX (54%) and13% of patients received a targeted agent: trastuzumab containing regimen (n = 26) or paclitaxel and ramucirumab (n = 5). Among all patients, the median OS from date of recurrence was 4.4 months. Patients with recurrence within six months had a poorer median survival (2.1 months) compared to patients with recurrence after six months (5.7 months; p &lt; 0.001). Median OS in patients with locoregional recurrence only was 7.4 months, distant recurrence only was 4.0 months, and both locoregional and distant recurrence was 3.4 months (p &lt; 0.001). Patients with prior primary treatment with resection had median OS of 4.2 months and patients with prior dCRT of 5.1 months (p = 0.605). Conclusions: The majority of patients had distant metastases at disease recurrence and a small proportion received systemic therapy after recurrence. Overall prognosis was poor, and survival outcomes were poorest among patients with recurrence within six months of initial curative treatment suggesting a worse biological tumor behaviour.

Risk of second primary malignancies among patients with carcinoid of the lung

ObjectivesLittle is known about the etiology of pulmonary carcinoids (PC). Associations with other types of cancer may identify shared risk factors but results from earlier studies were inconclusive. The aim of the present study was to explore the association between PC and other primary malignancies for identifying risk factors. MethodsA query of the nationwide Netherlands Cancer Registry generated data about patients diagnosed with PC from 1989 to 2018. The occurrence of second primary malignancies was evaluated separately for year 1 and years 2−30. The expected numbers of second primary malignancies were calculated using incidence reference tables, controlling for age, gender and period. Confidence intervals (95 % CI) for the ratio between observed and expected numbers (SIR: standardized incidence ratio) were calculated using Poisson distributions. ResultsIn a total of 2933 patients with PC, 425 consecutive primary malignancies were observed in 376 patients. Concomitant diagnoses in the first year mainly comprised lung (n = 59) and renal cancer (n = 14). Metachronous malignancies beyond the first year were most common for breast (n = 50), colorectal (n = 41), prostate (n = 32), and lung cancer (n = 29). Beyond year 1, the overall risk of second primary cancer in patients with PC was similar to the risk within the general population (n = 256, SIR = 1.12, 95 % CI 0.99–1.27). Increased risks were observed for soft tissue sarcoma (n = 5, SIR = 3.52, 95 % CI 1.14–8.22) and GEPNET (n = 4, SIR = 4.30, 95 % CI 1.17–11.01). ConclusionsConcomitant diagnosis of PC with other cancers is common, reflecting surveillance diagnostics. Apart from MEN-1 family history, no shared risk factors could be identified.

Contralateral breast cancer risk in patients with ductal carcinoma in situ and invasive breast cancer

We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I–III BC (N = 275,836) between 1989 and 2017 were identified from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04–1.17), and lower compared with stage I BC without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82–0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38 (95% CI = 1.35–1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46–3.13) when not screen-detected. The C-index was 0.52 (95% CI = 0.50–0.54) for invasive CBC prediction in DCIS patients. In conclusion, CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information is needed to differentiate CBC risks among DCIS patients.

The impact of prior malignancies on the development of second malignancies and survival in follicular lymphoma: A population‐based study

We assessed the impact of a prior malignancy diagnosis (PMD) – as a potential proxy for genetic cancer susceptibility – on the development of a second primary malignancy (SPM) and mortality in follicular lymphoma (FL) patients. From the nationwide Netherlands Cancer Registry, we selected all adult FL patients diagnosed in 1994‐2012 (n = 8028) and PMDs and SPMs relative to FL, with follow‐up until 2017. We constructed two Fine and Gray models – with death as a competing risk – to assess the association between a PMD and SPM incidence. A PMD was associated with an increased incidence of SPMs (subdistribution hazard ratio [SHR], 1.30; 95% confidence interval [CI], 1.03‐1.64) – especially carcinomas of the respiratory tract (SHR, 1.83; 95% CI, 1.10‐3.05) and cutaneous squamous cell carcinomas (SHR, 1.58; 95% CI, 1.01‐2.45) – and a higher risk of mortality in a multivariable model (HR, 1.43; 95% CI, 1.19‐1.71). However, when additionally adjusted for the receipt of systemic therapy and/or radiotherapy before FL diagnosis, only patients who received such therapies had an increased incidence of SPMs (SHR, 1.40; 95% CI, 1.02‐1.93). In conclusion, patients with a PMD had a higher rate of SPMs and mortality than those without a PMD, which might have resulted from therapy‐related carcinogenesis.