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Background: Data on CA-125 as a predictor of disease progression (PD) in ovarian cancer come predominantly from patients with platinum-sensitive disease receiving chemotherapy alone. We assessed concordance between CA-125-defined and RECIST-defined PD using data from the Gynecologic Cancer InterGroup (GCIG) randomized phase III AURELIA trial in platinum-resistant ovarian cancer (PROC)., Patients and Methods: Patients with PROC were randomized to receive single-agent chemotherapy with or without bevacizumab. PD by CA-125 was defined according to GCIG criteria (except that confirmatory CA-125 measurement was not required). This exploratory analysis included patients with RECIST PD and a CA-125 reading ≤28 days before and ≤21 days after RECIST-defined PD., Results: Of 218 eligible patients, only 94 (43%, 95% confidence interval 36% to 50%) had concordant RECIST and CA-125 PD status (42% in the chemotherapy-alone arm; 45% in the bevacizumab combination arm, P = 0.6). There was no evidence of CA-125-defined PD in the remaining 124 patients despite PD according to imaging. There were no significant differences in baseline characteristics between patients with PD defined by both RECIST and CA-125 and those with RECIST-only PD. CA-125 was even less sensitive in detecting PD in patients with early (<8 weeks after randomization) compared with later RECIST-defined PD (69% versus 53%, respectively, not meeting CA-125 criteria; P = 0.053). There was no significant difference in survival after PD in patients with concordant PD by RECIST and CA-125 versus those with PD only by RECIST. We validated our findings in an independent study population of PROC., Conclusions: In this platinum-resistant population, PD was typically detected earlier by imaging than by CA-125, irrespective of bevacizumab treatment. Disease status by CA-125 at the time of PD was not prognostic for overall survival. Regular radiologic assessment as well as symptom benefit assessment should be considered during PROC follow-up., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Patients with resectable oesophageal cancer are treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery within 3-8 weeks. In practice, surgery is often delayed for various reasons. The aim of this study was to evaluate whether delaying surgery beyond 8 weeks has an effect on postoperative morbidity, long-term survival, and pathologic response in patients treated for oesophageal ADC., Methods: Patients who underwent nCRT followed by surgery, for cT1-3, N0-3, M0 ADC between 2001 and 2014 were retrospectively included from a prospectively obtained database. Patients with a time from the end of nCRT to surgery (TTS) ≤8 weeks were compared with patients with a TTS >8 weeks., Results: Of 190 patients, 65 had a TTS ≤8 weeks, and 125 had a TTS >8 weeks. Patient characteristics were comparable for both groups, but patients with TTS >8 weeks exhibited higher ASA scores (p = 0.013) and more comorbidities (p = 0.007). Multivariate analysis revealed that TTS did not significantly influence postoperative morbidity, pathologic complete response rates, and five-year survival rates (42% in patients with TTS ≤8 weeks and 37% in patients with TTS >8 weeks)., Conclusions: Delaying surgery beyond 8 weeks after nCRT did not significantly influence postoperative morbidity, pathologic response, and survival in patients with non-metastatic ADC. Therefore, it appears reasonable to postpone surgery beyond 8 weeks in patients who have not yet recovered from nCRT. However, if the patient is fit for surgery, postponing surgery does not have any additional advantages., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to provide insight in the use, intensity and toxicity of therapy with capecitabine and oxaliplatin (CAPOX) and capecitabine monotherapy (CapMono) among elderly stage III colon cancer patients treated in everyday clinical practice., Methods: Data from the Netherlands Cancer Registry were used. All stage III colon cancer patients aged ≥70 years diagnosed in the southeastern part between 2005 and 2012 and treated with CAPOX or CapMono were included. Differences in completion of all planned cycles, cumulative dosages and toxicity between both regimens were evaluated., Results: One hundred ninety-three patients received CAPOX and 164 patients received CapMono; 33% (n = 63) of the patients receiving CAPOX completed all planned cycles of both agents, whereas 55% (n = 90) of the patients receiving CapMono completed all planned cycles (P < 0.0001). The median cumulative dosage capecitabine was lower for patients treated with CAPOX (163,744 mg/m(2), interquartile range [IQR] 83,397-202,858 mg/m(2)) than for patients treated with CapMono (189,195 mg/m(2), IQR 111,667-228,125 mg/m(2), P = 0.0003); 54% (n = 105) of the patients treated with CAPOX developed grade III-V toxicity, whereas 38% (n = 63) of the patients treated with CapMono developed grade III-V toxicity (P = 0.0026). After adjustment for patient and tumour characteristics, CapMono was associated with a lower odds of developing grade III-V toxicity than CAPOX (odds ratio 0.54, 95% confidence interval 0.33-0.89). For patients treated with CAPOX, the most common toxicities were gastrointestinal (29%), haematological (14%), neurological (11%) and other toxicity (13%). For patients treated with CapMono, dermatological (17%), gastrointestinal (13%) and other toxicity (11%) were the most common., Conclusion: CAPOX is associated with significantly more grade III-V toxicities than CapMono, which had a pronounced impact on the cumulative dosage received and completion of all planned cycles. In this light, CapMono seems preferable over CAPOX., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Lateral nodal disease is of major importance in the treatment of rectal cancer in the East, but a mostly neglected entity in the West. In this article, the treatment of recurrences in the lateral compartment (latLRs) in a national tertiary referral center is evaluated., Methods: Of 214 patients with locally recurrent rectal cancer who underwent multimodality treatment in the Catharina Hospital in the last 10 years, a total of 51 patients with latLR were selected (the latLR region was classified as upper, middle, or lower). Thirteen (25 %) of these patients underwent induction chemotherapy (ICT) prior to chemo(re)irradiation., Results: LatLRs occurred mainly after low and N+ primary tumors. Seven (14 %) patients had a complete response (pCR) and 28 (55 %) underwent an R0 resection. Patients with a lower latLR had the highest chance of undergoing an abdominoperineal resection and resection of anterior organs. ICT resulted in a 31 % pCR rate compared with 8 % without ICT (p = 0.039). Patients who received ICT had an 85 % R0 resection rate, while this was 45 % in patients who did not receive ICT (p = 0.013). The 5-year local re-recurrence (LRR) rate was 64.3 %, and overall survival (OS) was 34.2 %; the only factor improving these was an R0 resection. Five-year survival after multivariate analyses was 10.3 % after an R+ resection compared with 66.8 % after an R0 resection (p = 0.011)., Conclusions: LatLRs impose a major surgical challenge and result in high LRR and low OS. More R0 resections can possibly be achieved with ICT, which is the only factor that can improve LRR and OS.

Purpose: This study aimed to assess the longitudinal association between lifestyle factors, body mass index (BMI), and health-related quality of life (HRQoL) among colorectal cancer patients with (CRCDM+) and without diabetes (CRCDM-)., Methods: Data from a longitudinal study among CRC patients diagnosed between 2000 and 2009 were used. Clinical characteristics were retrieved from the Netherlands Cancer Registry and questionnaires were sent in 2010, 2011, and 2012 using the Patient Reported Outcomes Following Initial Treatment and Long term Evaluation of Survivorship (PROFILES) registry. Lifestyle (including moderate-to-vigorous physical activity (MVPA), smoking and alcohol use), BMI, diabetes status, and HRQoL were assessed in the questionnaire., Results: One thousand seven hundred thirty-nine (49 %) patients responded to ≥2 questionnaires, of whom 126 CRCDM+ and 789 CRCDM- patients were included. CRCDM+ patients had a higher BMI (29.1 ± 4.2 vs. 26.4 ± 3.7 kg/m(2)), whereas the number of alcohol users was lower (50 vs. 70 %, p value <0.0001) among CRCDM+ as compared to CRCDM- patients. Analyses adjusted for sociodemographic and cancer characteristics showed that CRCDM+ patients reported statistically significantly lower physical function (beta = -5.76; SE = 1.67), global QoL (beta = -4.31; SE = 1.48), and more symptoms of fatigue (beta = 5.38; SE = 1.95) than CRCDM- patients. However, these effects disappeared after adjustments for lifestyle factors and BMI which were all significant predictors of HRQoL. Additional adjustment for comorbidity further attenuated the main effect of DM on HRQoL., Conclusions: Diabetes was not independently associated with HRQoL but deteriorated HRQoL among CRCDM+ patients seem to be explained by an unhealthier lifestyle and other comorbid conditions. Moreover, residual confounding cannot be ruled out.

Background: Treatment possibilities for colorectal peritoneal metastases (PM) are increasing. It is however unclear how treatment choice and outcome are influenced by histological subtype and the presence of systemic metastases. Therefore, this study assessed the impact of histological subtype and systemic metastases on treatment choice and survival in patients with colorectal PM., Methods: This population-based study included patients with synchronous PM originating from colorectal adenocarcinoma (AC), mucinous adenocarcinoma (MC), or signet ring cell carcinoma (SRCC). Data of patients diagnosed between 2005 and 2014 were extracted from the National Cancer Registry (IKNL) of the Netherlands. Treatment strategy and survival were analyzed with logistic regression and cox proportional hazard analyses., Results: In total, 5516 patients were included, of whom 71.8% had an AC, 21.2% an MC, and 7.0% had an SRCC. The use of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) was dependent on histological subtype and the presence of systemic metastases, and increased over time, especially in AC and MC patients. The relative survival gain of CRS + HIPEC, corrected for systemic metastases, was comparable in AC, MC, and SRCC patients (hazard ratio: 0.17, 0.21, and 0.13, respectively). Compared to supportive care only, the absolute survival gain was 30, 35, and 18 months, respectively. Systemic therapy improved survival in all histological subtypes., Conclusions: Histological subtype and the presence of systemic metastases strongly influenced treatment choice and survival in patients with synchronous colorectal PM. These results can be used to optimize treatment strategy for patients with synchronous colorectal PM., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Most patients with colorectal cancer (CRC) presenting with peritoneal carcinomatosis (PC) rely on palliative systemic treatment options. However, data on the use and effect of systemic treatment strategies, including targeted agents for the palliative treatment of colorectal PC, are lacking. We conducted a nationwide population-based study with data from the period in which the targeted agent bevacizumab was introduced in the Netherlands., Patients and Methods: The present study included all patients diagnosed from 2007 to 2014 with synchronous PC from CRC treated with only palliative systemic therapy. We assessed the use of bevacizumab, the standard choice of targeted treatment, in addition to first-line chemotherapy. Multivariable logistic regression analyses were performed to calculate the predictors for the additional prescription of bevacizumab. Survival estimates were calculated, and multivariable Cox analyses were performed to estimate the hazard ratios (HRs) of death stratified by the treatment received., Results: A total of 1235 patients received palliative chemotherapy, of whom 436 also received bevacizumab (35%). Patients aged ≥ 75 years and patients with PC from colonic tumors were less likely to receive chemotherapy plus bevacizumab. The addition of bevacizumab to palliative chemotherapy was associated with an improved overall median survival of 7.5 versus 11 months in both patients with isolated PC and those with concomitant extraperitoneal metastases. The improvement remained after adjustment for patient and tumor characteristics (HR, 0.7; 95% confidence interval, 0.64-0.83)., Conclusion: The results of the present nationwide population-based study support the rationale for bevacizumab in addition to palliative chemotherapy for patients with PC of CRC and underline the need for ongoing efforts to precisely determine the role of targeted therapy in the treatment of PC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: In pancreatic surgery, a relation between surgical volume and postoperative mortality and overall survival (OS) has been recognized, with high-volume centers reporting significantly better survival rates. We aimed to explore the influence of hospital volume on administration of palliative chemotherapy and OS in the Netherlands., Methods: Patients diagnosed between 2007 and 2011 with metastatic pancreatic cancer were identified in the Netherlands Cancer Registry. Three types of high-volume centers were defined: high-volume (1) incidence center, based on the number of patients diagnosed with metastatic pancreatic cancer, (2) treatment center based on number of patients with metastatic pancreatic cancer who started treatment with palliative chemotherapy and (3) surgical center based on the number of resections with curative intent for pancreatic cancer. Independent predictors of administration of palliative chemotherapy were evaluated by means of logistic regression analysis. The multivariable Cox proportional hazard model was used to assess the impact of being diagnosed or treated in high-volume centers on survival., Results: A total of 5385 patients presented with metastatic pancreatic cancer of which 24 % received palliative chemotherapy. Being treated with chemotherapy in a high-volume chemotherapy treatment center was associated with improved survival (HR 0.76, 95 % CI 0.67-0.87). Also, in all patients with metastatic pancreatic cancer, being diagnosed in a high-volume surgical center was associated with improved survival (HR 0.74, 95 % CI 0.66-0.83)., Conclusions: Hospital volume of palliative chemotherapy for metastatic pancreatic cancer was associated with improved survival, demonstrating that a volume-outcome relationship, as described for pancreatic surgery, may also exist for pancreatic medical oncology.

Background: Patient-reported outcomes (PROs) are amongst the most relevant outcome measures in pancreatic cancer care and research. However, it is unknown which out of the numerous PROs are most important to patients and health care professionals (HCPs) in this setting. The aim of this study was to identify a core set of PROs to be incorporated in a nationwide prospective multidisciplinary pancreatic cancer registry., Patients and Methods: We performed a two-round Delphi survey among 150 patients diagnosed with pancreatic or periampullary cancer (treated either with curative intent or in palliative setting) and 78 HCPs (surgeons, medical oncologists, gastroenterologists, radiotherapists, nurses, and dietitians) in The Netherlands. In round 1, participants were invited to rate the importance of 53 PROs, which were extracted from 17 different PRO measures and grouped into global domains, on a 1-9 Likert scale. PROs rated as very important (score 7-9) by the majority (≥ 80%) of curative and/or palliative patients as well as HCPs were considered sufficiently important to be incorporated in the core set. PROs not fulfilling these criteria in round 1 were presented again to the participants in round 2 along with individual and group feedback., Results: A total of 97 patients (94%) in curative-intent setting, 38 patients (81%) in palliative setting and 73 HCPs (94%) completed both rounds 1 and 2. After the first round, 7 PROs were included in the core set: general quality of life, general health, physical ability, satisfaction with caregivers, satisfaction with services and care organisation, coping and defecation. After the second round, 10 additional PROs were added: appetite, ability to work/do usual activities, medication use, weight changes, fatigue, negative feelings, positive feelings, fear of recurrence, relationship with partner/family, and pancreatic enzyme replacement therapy use., Conclusion: This study provides a core set of PROs selected by patients and HCPs, which may be incorporated in pancreatic cancer care and research. Validation outside the Dutch context is recommended for generalisation and use in international studies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Although the efficacy of bevacizumab has been established in patients with metastatic colorectal cancer (mCRC), population-based studies are needed to gain insight into the actual implementation of bevacizumab in daily practice. Since these studies are lacking for patients with metachronous metastases, the aim of this study is to evaluate the current role of bevacizumab in the treatment of metachronous metastases of CRC., Methods: Data on the use of bevacizumab as palliative treatment of metachronous metastases were collected for patients diagnosed with M0 CRC between 2003 and 2008 in the Eindhoven Cancer Registry (n = 361). Median follow up was 5.3 years., Results: One hundred eighty-five patients received bevacizumab in addition to first-line palliative chemotherapy (51%), ranging from 36% to 80% between hospitals of diagnosis (p < 0.0001). Combined cytostatic regimens (CAPOX/FOLFOX in 97%) were prescribed in the majority of patients (63%) and were associated with a higher odds for additional treatment with bevacizumab than single-agent cytostatic regimens (OR 9.9, 95% CI 5.51-18.00). Median overall survival (OS) rates were 21.6 and 13.9 months with and without the addition of bevacizumab to palliative systemic treatment respectively (p < 0.0001). The addition of bevacizumab to palliative chemotherapy was associated with a reduced hazard ratio for death (HR 0.6, 95% CI 0.45-0.73) after adjustment for patient- and tumor characteristics and the prescribed chemotherapeutic regimen., Conclusion: Bevacizumab is adopted as a therapeutic option for metachronous metastasized CRC mainly in addition to first-line oxaliplatin-based regimens, and was associated with a reduced risk of death. The presence of inter-hospital differences in the prescription of bevacizumab reflected important differences in attitude and policies in clinical practice. Ongoing efforts should be made to further define the position of targeted agents in the treatment of metastatic colorectal cancer.

Background: We conducted a population-based study to investigate long-term survival in patients diagnosed with a (suspected) pancreatic adenocarcinoma., Methods: All patients diagnosed with a pancreatic adenocarcinoma or with a pathologically unverified tumour of the pancreas between 1993 and 2008 in the South of the Netherlands were selected from the Netherlands Cancer Registry (NCR). Medical charts of patients who were alive five years or longer since diagnosis were reviewed., Results: A total of 2 564 patients were included, of whom 1 365 had a pancreatic adenocarcinoma and 1 199 had a pathologically unverified pancreatic tumour. Five-year survival of patients with pathologically verified adenocarcinomas was 1.7% (24 of 1 365 patients). Twenty-one-one of these 24 long-term survivors were among the 207 cases that underwent surgical resection as initial treatment; five-year survival after resection thus being 10.1%. Half of the long-term survivors who underwent surgical resection still eventually died of recurrent disease. Five-year survival among patients with clinically suspected but microscopically unverified pancreatic tumours was 1.3% (16 of 1 199 patients). In 15 of these 16 long-term survivors the initial clinical diagnosis was revised: 14 had benign disease and one a premalignant tumour., Conclusions: Long-term survival among patients with pancreatic adenocarcinoma is extremely rare. As long-term survival in clinically suspected but pathologically unverified cancer is very unlikely, repeated fine needle aspiration or, preferably, histological biopsy is recommended in order to establish an alternative diagnosis in patients who survive longer than expected (more than 6-12 months).

Combining chemotherapy and targeted therapies has resulted in an enhanced survival in metastatic colorectal cancer (mCRC) patients. However, the result of this palliative treatment in patients with metachronous peritoneal carcinomatosis (PC) remains unknown. The current population-based study aims to investigate the use and effect of palliative systemic treatment in patients with metachronous PC of colorectal origin. Data on metachronous PC were collected between 2010 and 2011 for all patients who were diagnosed with M0 colorectal cancer between 2003 and 2008 in the Dutch Eindhoven Cancer Registry. Patient demographics and detailed data on chemotherapeutic treatment were collected and compared. Ninety-two patients with metachronous PC received chemotherapy in a palliative setting compared to 94 patients without treatment. In 36 patients, Bevacizumab was added to the treatment (39%). Overall survival was 3.4, 13, and 20.3 months in the no treatment, systemic treatment and systemic treatment + Bevacizumab respectively (P < 0.001). Male gender was a positive predictor and right sided primary tumor location a negative predictor of receiving bevacizumab. Approximately 40% of patients with metachronous PC received bevacizumab in addition to chemotherapy. Treatment with systemic chemotherapy in combination with bevacizumab may increase survival in a patients with metachronous colorectal PC.

Background: With evolving treatment possibilities for peritoneal metastases (PM) from colorectal cancer (CRC), adequate prognostication and patient selection for treatment becomes increasingly important. We investigated the prognostic relevance of commonly identified histological subtypes in PM of CRC (adenocarcinoma [AC], mucinous AC [MC], and signet-ring cell carcinoma [SC]), which is currently unclear., Patients and Methods: This study involved 4277 patients diagnosed with synchronous PM from CRC between 2005 and 2012 in The Netherlands. Kaplan-Meier analysis and log-rank testing were performed to estimate survival. Subsequently a Cox proportional hazard model was used to calculate hazard ratios for the risk of death., Results: Most of the CRC patients were diagnosed with AC (n = 3008; 70%), whereas MC and SC were found in 958 (22%) and 311 (7%) patients, respectively. SC was associated with the highest risk of death in colon and rectal cancer, with median survival rates of respectively, 6.6 and 6.9 months. For MC, median survival varied from 10.9 months in colon and 9.8 months in rectal cancer (P > .05). In colon cancer, MC was associated with a significantly lower risk of death compared with AC (hazard ratio, 0.9; 95% confidence interval, 0.79-0.95). In rectal cancer, no such effect was observed. AC was associated with a significantly poorer survival rate in the case of primary colonic tumor localization (7.4 months in colon vs. 10.9 months in rectal cancer)., Conclusion: Histological subtype is an important prognostic factor in patients with synchronous PM of colorectal origin. This knowledge will aid clinicians in counseling of patients and clinical decision-making regarding possible treatment options., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Currently available data suggest that delaying the start of adjuvant chemotherapy in colon cancer patients has a detrimental effect on survival. We analysed which factors impact on the timing of adjuvant chemotherapy and evaluated the influence on overall survival (OS)., Patients and Methods: Stage III colon cancer patients who underwent resection and received adjuvant chemotherapy between 2008 and 2013 were selected from the Netherlands Cancer Registry. Timing of adjuvant chemotherapy was subdivided into: ⩽ 4, 5-6, 7-8, 9-10, 11-12 and 13-16 weeks post-surgery. Multivariable regressions were performed to assess the influence of several factors on the probability of starting treatment within 8 weeks post-surgery and to evaluate the association of timing of adjuvant chemotherapy with 5-year OS., Results: 6620 patients received adjuvant chemotherapy, 14% commenced after 8 weeks. Factors associated with starting treatment after 8 weeks were older age (Odds ratio (OR) 65-74 versus < 65 years 1.3 (95% confidence interval (CI): 1.14-1.58); OR ⩾ 75 versus < 65 years 1.6 (1.25-1.94)), emergency resection (OR 1.8 (1.41-2.32)), anastomotic leakage (OR 8.1 (6.14-10.62)), referral to another hospital for adjuvant chemotherapy (OR 1.9 (1.36-2.57)) and prolonged postoperative hospital admission (OR 4.7 (3.30-6.68)). Starting 5-8 weeks post-surgery showed no decrease in OS compared to initiation within 4 weeks (Hazard ratio (HR) 5-6 weeks 0.9 (0.79-1.11); HR 7-8 weeks 1.1 (0.91-1.30)). However, commencing beyond 8 weeks was associated with decreased OS compared to initiation within 8 weeks (HR 9-10 weeks 1.4 (1.21-1.68); HR 11-12 weeks 1.3 (1.06-1.59); HR 13-16 weeks 1.7 (1.23-2.23))., Conclusion: Our data support initiating adjuvant chemotherapy in stage III colon cancer patients within 8 weeks post-surgery., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Isolated pancreatic involvement is a rare initial presentation in patients with ANCA-associated vasculitis. We report a patient with a suspected malignant pancreatic mass, referred to our hospital for pancreaticoduodenectomy. However, the pancreatic mass proved to be the initial manifestation of ANCA-associated vasculitis.

Background: The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation., Methods: In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637., Findings: Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56-0·81, p<0·0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 [23%] patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups., Interpretation: Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life., Funding: Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study is to identify doctor-related factors determining the decision-making for adjuvant chemotherapy for patients with stage III colon cancer aged ≥75years., Materials and Methods: 21 surgeons and 15 medical oncologists from 10 community hospitals were asked to complete a short questionnaire including tick-box questions regarding motives for non-referral/non-treatment, consultation of geriatricians, chemotherapy schemes prescribed and an open question regarding tolerability of chemotherapy., Results: 29 medical specialists returned a completed questionnaire (response 81%). The motives for non-referral/non-treatment reported most often were comorbidity/bad general health condition of the patient; surgical complications; and treatment offered but refused by patient/family. 39% of the surgeons and 55% of the medical oncologists reported consultation of a geriatrician in 2-30% of their decisions. CAPOX and capecitabine were reported by medical oncologists as the most frequently prescribed regimens. Factors that influenced the decision for monotherapy or combination therapy were comorbidity; general health condition of the patient; and toxicity profile of the chemotherapeutics. In general, medical oncologists defined grade ≤2 toxicities as tolerable, with the exception of neuropathy, for which grade ≤1 toxicity was accepted., Conclusions: In case medical oncologists prescribe adjuvant chemotherapy to elderly patients with stage III colon cancer, the chemotherapy schemes used are in line with clinical guidelines and they agree on acceptable levels of toxicity. However, the variation among surgeons and medical oncologists in motives for non-referral, non-treatment and consultation of geriatricians when deciding on adjuvant chemotherapy for elderly patients with stage III colon cancer, shows the complexity and need for specific knowledge., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Population-based data on the percentage of colorectal cancer (CRC) patients with synchronous peritoneal carcinomatosis (PC) being treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are currently lacking. The current population-based study describes trends in the use of CRS-HIPEC in the Netherlands, one of the first countries where CRS and HIPEC was introduced., Methods: All patients diagnosed with synchronous PC of CRC between 2005 and 2012 were extracted from the Netherlands Cancer Registry (n = 4623). Patients with primary appendiceal cancer were excluded resulting in a study population of 4430 patients. Trends in the use of CRS-HIPEC over time were analyzed by means of a Cochrane-Armitage trend test. Survival proportions were calculated as the time between diagnosis and date of death or last follow-up (January 2014)., Results: Of the total 4430 patients with synchronous PC, 297 (6.4%) underwent treatment with CRS-HIPEC. The proportion of colorectal PC patients receiving CRS-HIPEC increased significantly over time from 3.6% in 2005-2006 to 9.7% in 2011-2012 (p < 0.0001). Overall median survival (MS) for patients treated with CRS-HIPEC was 32.3 months, whereas MS rates were respectively 12.6, 6.1 and 1.5 for months palliative chemotherapy with/without surgery, palliative surgery and best supportive care., Conclusion: The proportion of patients diagnosed with synchronous PC from CRC treated with CRS-HIPEC has increased significantly over time and currently almost 10% of PC patients are treated with CRS-HIPEC. Median survival in this population based group is 32.3 months., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: This population-based study assessed which factors were associated with pathological verification of pancreatic cancer., Methods: All patients diagnosed with a malignancy of the pancreas between 1993 and 2010 in the South of the Netherlands (N=3321) were included., Results: Pancreatic cancer was pathologically verified in 59% of patients. The proportion of verification increased over time from 56% in 1993-1996 to 69% in 2009-2010 (p<0.0001). High rates of verification were found among young patients (<50 years vs. 60-69 yrs: adjusted odds ratio (ORadj) 3.2 (95% CI: 1.9-5.4)), patients with a high socioeconomic status (high vs. low: ORadj 1.3 (95% CI: 1.1-1.7)), patients with metastatic disease (metastatic vs locoregional: ORadj 3.2 (95% CI: 2.7-3.8)) and patients treated with chemotherapy (yes vs. no: ORadj 2.4 (95% CI: 1.8-3.2)). The most favorable prognosis was found in patients with verified locoregional disease (median overall survival (mOS) 7.6 months, 95% CI: 7.1-8.6). Patients with unverified metastatic disease carried the worst prognosis (mOS 1.7 months, 95% CI: 1.4-2.0)., Conclusion: Verification by pathology remains preferable and desirable whenever possible. However, the median survival rate exhibited by patients without verification suggests that the vast majority of patients suffered from true invasive pancreatic cancer. This may justify treatment decisions even in the absence of pathologic verification in selected patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: A large proportion of patients with pancreatic cancer presents with metastatic disease. We conducted a population-based study to evaluate trends in treatment and survival of patients with metastatic pancreatic cancer., Methods: We included all patients diagnosed with pancreatic cancer between 1993 and 2010 in the South of the Netherlands (N=3099). Multivariable logistic regression analysis was conducted to evaluate trends in treatment with chemotherapy. Crude overall survival according to period of diagnosis was analyzed, and independent risk factors for death were identified., Results: Forty-eight percent of the patients (N=1494) were diagnosed with metastatic disease. The percentage of patients being diagnosed with metastatic disease increased during the study period from 35% in 1993-1996 to 59% in 2009-2010 (p<0.0001). Overall, 18% of these patients received chemotherapy. The prescription of palliative chemotherapy almost tripled from 10% to 27% (p<0.0001). Treatment largely depended on age, ranging from 38% among patients aged <50 years [compared to 60-69 years: adjusted odds ratio (ORadj) 2.5 (95% CI 1.4-4.2)] to 1% among patients aged ≥80 years [compared to 60-69 years: ORadj 0.04 (95% CI 0.0-0.2)]. Patients were more likely to receive chemotherapy if they had a high socioeconomic status [ORadj 2.0 (95% CI 1.3-3.1)], and if diagnosis was pathologically verified [no verification vs. verification: ORadj 0.3 (95% CI 0.2-0.5)]. The administration of chemotherapy varied widely between 10 hospitals (5-34%, p<0.0001). The median overall survival of patients with metastatic pancreatic cancer remained 9-11 weeks., Conclusion: A growing proportion of pancreatic cancer patients presented with metastatic disease. Usage of palliative chemotherapy increased over time, but median survival remained 9-11 weeks. In the near future, it should be evaluated if the recently introduced regimens have an impact on population-based survival.

Objectives: We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT., Background: Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently "sterilize" regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful., Methods: Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups., Results: One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P=0.007), but not in the multimodality arm (hazard ratio 1.00; P=0.98)., Conclusions: The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

Background: Many patients with locally recurrent rectal cancer receive radiotherapy for the treatment of the primary tumour. It is unclear whether reirradiation is safe and effective when a local recurrence develops. The aim of this study was to evaluate the toxicity and oncological outcome of reirradiation in patients with locally recurrent rectal carcinoma., Methods: From March 1994 until December 2013, data on patients with locally recurrent rectal cancer (without distant metastasis) were entered into a database. Patients were reirradiated with a reduced dose of 30 Gy and received an intraoperative electron radiotherapy boost during surgery. Morbidity associated with radiotherapy, postoperative complications and oncological outcome were evaluated., Results: Clear margins (R0) were obtained in 75 (55·6 per cent) of the 135 patients who were reirradiated. Forty-six patients developed serious postoperative complications and the 30-day mortality rate was 4·6 per cent. Multivariable analysis showed that margin status was the main factor influencing oncological outcome (hazard ratio for overall survival 2·51 for R1 and 3·19 for R2 versus R0 resection; both P < 0·001). There was no significant difference in survival between the reirradiated group and a group of 113 patients who had full-course irradiation (5-year overall survival rate 34·1 and 39·1 per cent respectively; P = 0·278). Both reirradiation and full-course irradiation were associated with better survival than no irradiation in a historical control group of 24 patients (5-year overall survival rate 23 per cent; P = 0·225 and P = 0·062)., Conclusion: Reirradiation (with concomitant chemotherapy) has few side-effects and complements radical resection of recurrent rectal cancer., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Introduction: Population-based data on metachronous peritoneal carcinomatosis (PC) after curative resection of colorectal origin are scarce. The aim of this study was to investigate the incidence of and risk factors for developing metachronous PC from colorectal cancer as well as survival since diagnosis of PC., Methods: Data on metachronous metastases were collected between 2010 and 2011 for all patients diagnosed with M0 colorectal cancer between 2003 and 2008 in the Dutch Eindhoven Cancer Registry. Median follow-up was 5.0 years. Survival was defined as time from metastases diagnosis to death., Results: Of the 5671 colorectal cancer patients, 1042 (18%) were diagnosed with metachronous metastases of whom 197 (19%) developed metachronous PC. The peritoneal surface was the only site of metastasis in 81 (41%) patients while 116 (59%) patients were diagnosed with both PC and metastases elsewhere. Median survival after diagnosis of PC was 6 months compared to 15 months for patients with distant metastases in other organs. Patients with an advanced primary tumour stage, positive lymph nodes at initial diagnosis, primary mucinous adenocarcinoma, positive resection margin and a primary tumour located in the colon were at increased risk of developing metachronous PC., Conclusion: Of the colorectal cancer patients who developed metachronous metastases, approximately one fifth is diagnosed with PC. Prognosis of these patients is poor with a median survival of 6 months after diagnosis. Identifying patients at high risk for developing metachronous PC is important as it may contribute to more accurate patient information, tailor-made follow-up schemes, and more adequate treatment., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: This study aimed to provide information on timing, anatomical location, and predictors for metachronous metastases of colorectal cancer based on a large consecutive series of non-selected patients., Methods: All patients operated on with curative intent for colorectal cancer (TanyNanyM0) between 2003 and 2008 in the Dutch Eindhoven Cancer Registry were included (N=5671). By means of active follow-up by the Cancer Registry staff within ten hospitals, data on development of metastatic disease were collected. Median follow-up was 5.0 years., Results: Of the 5671 colorectal cancer patients, 1042 (18%) were diagnosed with metachronous metastases. Most common affected sites were the liver (60%), lungs (39%), extra-regional lymph nodes (22%), and peritoneum (19%). 86% of all metastases was diagnosed within three years and the median time to diagnosis was 17 months (interquartile range 10-29 months). Male gender (HR=1.2, 95%CI 1.03-1.32), an advanced primary T-stage (T4 vs. T3 HR=1.6, 95%CI 1.32-1.90) and N-stage (N1 vs. N0 HR=2.8, 95%CI 2.42-3.30 and N2 vs. N0 HR=4.5, 95%CI 3.72-5.42), high-grade tumour differentiation (HR=1.4, 95%CI 1.17-1.62), and a positive (HR=2.1, 95%CI 1.68-2.71) and unknown (HR=1.7, 95%CI 1.34-2.22) resection margin were predictors for metachronous metastases., Conclusions: Different patterns of metastatic spread were observed for colon and rectal cancer patients and differences in time to diagnosis were found. Knowledge on these patterns and predictors for metachronous metastases may enhance tailor-made follow-up schemes leading to earlier detection of metastasized disease and increased curative treatment options., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background and Objectives: Medium- and long-term survival is low in esophageal cancer (EC) patients, which is thought to be due to tumor characteristics. Our aim was to determine both tumor- and non-tumor-related characteristics affecting survival in these patients., Methods: Patients with primary EC between 1990 and 2008 in the southern part of the Netherlands were identified. Multivariable logistic regression was used to identify determinants of survival., Results: In total, 703 patients with EC were included for the 1-year, 551 for the 3-year and 436 for the 5-year survival analysis. Poor 1-year survival was independently associated with chemoradiation (compared to surgery), positive lymph nodes (N1-stage) and 1 or ≥2 comorbidities. Adenocarcinoma (EAC) compared to squamous cell carcinoma was significantly associated with a better 1-year survival. Poor 3- and 5-year survival was associated with N1-stage and chemoradiation. Positive prognostic factors for 3- and 5-year survival were neoadjuvant therapy and female gender., Conclusion: Both tumor-related (negative lymph nodes and EAC histology) and non-tumor-related factors (surgery, neoadjuvant therapy, and female gender) are associated with a better survival of EC. Although it is not clear how histology and gender affect EC survival, knowledge of these factors may be relevant for clinical decision making.

Aims: To report our clinical experience of panitumumab monotherapy as a second-line treatment for patients with metastatic colorectal cancer (mCRC)., Materials and Methods: This retrospective, descriptive study included a series of consecutive patients receiving panitumumab monotherapy (6 mg/kg 2 weekly) at a single centre in the Netherlands between June 2009 and November 2011. All patients had wild-type KRAS tumours, had progressed during first-line fluoropyrimidine-based therapy and were not candidates for, or refused, standard second-line therapy (usually irinotecan in the Netherlands). Prophylactic medication was given for epidermal growth factor receptor inhibitor-associated skin toxicities., Results: Thirty-one patients were treated during this period. The most commonly administered first-line mCRC regimen was capecitabine/oxaliplatin/bevacizumab (18/31 patients; 58.1%). Patients received a mean of 7.9 (range 1-18) panitumumab cycles. The median progression-free survival was 3.4 (95% confidence interval 2.4, 4.4) months. The median overall survival estimates were 11.4 (95% confidence interval 1.2, 21.6) months from the initiation of panitumumab monotherapy. Ten patients experienced partial responses according to Response Evaluation Criteria In Solid Tumors (RECIST; objective response rate: 32.3%); disease was controlled (objective response or stable disease) in 15 patients (48.4%). Carcinoembryonic antigen (CEA) responses (two consecutive ≥10% decreases from baseline) occurred in 11/29 patients (37.9%); all of whom had >50% decreases in CEA levels. All patients with an objective response at week 12 had CEA reductions at weeks 6 and 12. The only adverse events were grade 1/2 skin toxicities (61.3%) and gastrointestinal complaints (6.5%); three other patients (9.7%) experienced both skin and gastrointestinal complaints., Conclusion: Panitumumab monotherapy seems to be a safe and active second-line treatment for patients with wild-type KRAS mCRC, with activity in line with that seen for irinotecan monotherapy, but with less toxicity. CEA may provide a useful early indicator of response to panitumumab., (Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Gastric cancer often presents in a metastasized stage. We conducted a population-based study to evaluate trends in systemic treatment and survival of metastatic noncardia gastric cancer., Patients and Methods: All patients with noncardia adenocarcinoma of the stomach, diagnosed between 1990 and 2011 in the Eindhoven Cancer Registry area in the Netherlands were included (N = 4797). We conducted multivariable logistic regression analysis to evaluate trends in administration of palliative chemotherapy and multivariable proportional hazards regression analyses to evaluate trends in crude overall survival., Results: The proportion of patients presenting with metastatic gastric cancer increased from 24% in 1990 to 44% in 2011 (P < 0.0001). The use of palliative chemotherapy increased, from 5% in 1990 to 36% in 2011, with a strong increase in particular after 2006 (P < 0.0001). Younger patients [<50 years: adjusted odds ratio (ORadj) 3.9, P < 0.001; 50-59 years: ORadj 1.7, P = 0.01] and patients with a high socioeconomic status (ORadj 1.7, P = 0.01) more often received chemotherapy. In contrast, older patients (70-79 years: ORadj 0.3, P < 0.001; 80+ years: ORadj 0.02, P < 0.001), patients with comorbidity (ORadj 0.6, P = 0.03), linitis plastica (ORadj 0.5, P = 0.03) and multiple distant metastases (ORadj 0.5, P = 0.01) were less often treated with chemotherapy. A large hospital variation was observed in the administration of palliative chemotherapy (9%-27%). Median overall survival remained constant between 15 [95% confidence interval (CI) 11.9-17.7] and 17 (95% CI 15.0-20.0) weeks (P = 0.10)., Conclusions: The increased administration of chemotherapy in patients with metastatic gastric cancer did not lead to an increase in population-based overall survival. Identification of the subgroup of patients which benefits from palliative chemotherapy is of utmost importance to avoid unnecessary treatment.

Background: Little is known about the effects of adjuvant chemotherapy on the risk of distant recurrence in elderly with stage III colon cancer, treated in daily practice., Patients and Methods: One thousand two hundred and ninety-one stage III colon cancer patients diagnosed in the southern Netherlands between 2003 and 2008 were included. Propensity score matching was applied to create a subsample to reduce bias caused by differences between patients receiving adjuvant chemotherapy and patients not receiving adjuvant chemotherapy. For both the total study population and the propensity score matched sample, Cox regression analysis was used to discriminate independent risk factors for distant recurrence., Results: Adjuvant chemotherapy (CT) was correlated with a reduced risk of distant recurrence in both the total study population [hazard ratio (HR) CT versus nCT 0.55, 95% confidence interval (CI) 0.42-0.70] and in the propensity score matched sample (HR CT versus nCT 0.46, 95% CI 0.33-0.63). In separate analyses for patients aged <75 and ≥75 years, the effect of adjuvant chemotherapy on the risk of distant recurrence remained comparable for both age groups (HR CT versus nCT 0.50, 95% CI 0.37-0.68 and 0.57, 95% CI 0.36-0.90, respectively)., Conclusion: Distant recurrence risks at higher age definitely warrant consideration of adjuvant chemotherapy for elderly stage III colon cancer patients. This decision should be based on a multidisciplinary and functional assessment of the patient, not on age.

There is little information available on the patterns of chemotherapy regimens administered in daily practice to patients with early stage and metastatic or recurrent breast cancer. To determine the trends in type of chemotherapy regimens used in breast cancer patients, newly diagnosed breast cancer patients in the period 2000-2008 who received chemotherapy were identified from the Eindhoven Cancer Registry (ECR) and linked to the PHARMO RLS, including data on, e.g., in- and outpatient drug use. Chemotherapy regimens were classified based on the received combinations and sequences. Trends in the distribution of adjuvant chemotherapy regimens (for early-stage breast cancer) and palliative chemotherapy regimens (for metastatic or recurrent breast cancer) were determined and stratified by Her2/neu status when possible. In this study, 422 patients diagnosed with early-stage breast cancer received adjuvant chemotherapy. The use of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) decreased from 90% in 2000 to almost none since 2005. Administration of regimens that included anthracyclines increased from 4% in 2000 to 96% in 2005, but decreased to 68% in 2008. The use of trastuzumab- and taxane-containing regimens (with or without anthracyclines) increased from 2005 onwards to 24% and 34%, respectively, in 2008. Among the 82 breast cancer patients who received palliative chemotherapy at diagnosis or after breast cancer recurrence, the use of CMF and anthracyclines (without taxanes) decreased, while the use of taxanes (with or without anthracyclines) increased (26% in 2008). Trastuzumab was used as palliative chemotherapy from 2003 onwards, with 22% of the metastatic breast cancer patients receiving trastuzumab-containing regimens in 2008, and bevacizumab was administered since 2007 with 19% of the patients receiving bevacizumab-containing regimens in 2008. In conclusion, major changes have taken place in the chemotherapeutic treatment of patients with early and recurrent breast cancer. These changes reflect the key findings from large clinical trials, as incorporated in the Dutch guidelines., (© 2013 Wiley Periodicals, Inc.)

Objectives: Combination chemotherapy regimens have shown promising results in patients with metastatic colorectal cancer. However, only very few studies have studied the effect of palliative chemotherapy in peritoneal carcinomatosis (PC) and no data are present incorporating biological therapies in the treatment of PC in colorectal cancer., Methods: By means of merging with the regional Eindhoven Cancer Registry, all consecutive patients diagnosed with synchronous PC of colorectal origin since the year 2000 treated with palliative chemotherapy in our hospital were included. Data on chemotherapeutic agents used were collected retrospectively. The effect of biological therapies on survival was investigated., Results: Fifty consecutive patients were included. Chemotherapeutic treatment consisted mainly of 5-fluorouracil-based chemotherapy with oxaliplatin. In 22 patients biological therapies were added. Overall survival was 12.5 months [95% confidence interval (CI), 9.2-15.5]. In patients receiving chemotherapy in combination with a biological therapy, overall survival was significantly prolonged as compared with those treated without (18.2 months, 95% CI, 9.5-27.0 vs. 10.1 mo, 95% CI, 6.2-14.1, respectively; P=0.001). Prolongation of survival of patients receiving biological therapies in first-line treatment was even more pronounced, being 22.4 months (95% CI, 15.0-29.5). Similar effects were observed on progression-free survival., Conclusions: Systemic chemotherapy, once regarded as futile in patients suffering from PC, resulted in an overall survival of 12 months in this unselected group of PC-patients. Addition of biological therapies in the first line of treatment prolonged overall survival to 22.4 months. Although the results of this small study should be interpreted with caution, this promising finding warrants further research.

Background: Patients with metastasized colorectal cancer (mCRC) have different information needs compared with patients with nonmetastatic colorectal cancer (CRC). Appropriate information provision leads to better patient reported outcomes for patients with nonmetastatic disease., Objective: To measure the perceived level of, and satisfaction with, information received by patients with mCRC as compared with those with nonmetastatic (stage I,II,III) CRC. Also, associations of information provision with health status, anxiety, depression, and illness perceptions were investigated., Methods: A cross-sectional population-based survey was conducted. All CRC patients diagnosed between 2002 and 2007 according to the Eindhoven Cancer Registry (ECR) were selected. Response rate was 75% (n=1159, of which 139 had mCRC). Participants completed questionnaires on information provision (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-INFO25), health status (Short Form-36), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), and illness perceptions (Brief Illness Perception Questionnaire [B-IPQ])., Results: The perceived receipt of information was quite comparable between CRC patients with and without mCRC. Only perceived receipt of treatment information was higher for patients with mCRC (45 versus 37; p<0.01). Sixty percent of the patients with mCRC were satisfied with the amount of received information and almost 30% wanted to receive more information. The perceived receipt of more disease information and information about other services was associated with worse health outcomes, whereas satisfaction with the received information was not associated with health outcomes., Conclusion: The findings of this study indicate that some improvements can be made in the provision of information to patients with mCRC. Adequate assessment of information needs of mCRC patients, as well as appropriate responses to these needs by providing the information in an appropriate way could possibly lead to improvements in patient satisfaction.

Background: This multicentre, randomised, open label, phase II/III study aimed to investigate the potential benefit of adding risedronate (R) to docetaxel (D) in patients with metastatic Castration Resistant Prostate Cancer (CRPC)., Patients and Methods: CRPC patients with bone metastasis were randomly assigned to receive D 75 mg/m(2) every 3 weeks and prednisone as first line chemotherapy, with or without R 30 mg oral once daily. The primary end-point was time to progression (TTP). A composite end-point of objective progression by RECIST criteria, PSA progression, or pain progression, whichever occurred first, was applied. The study had 80% power to detect an improvement of 30% in median TTP in the DR group (two-sided α=0.05)., Results: Five hundred and ninety-two men (301 D versus 291 DR) were randomised. TTP was 7.4 [D] versus 6.5 [DR] months (p=0.75). PSA and pain response rates were similar, 66.3% [D] versus 65.9% [DR] and 27.9% [D] versus 31.2% [DR], respectively. Median overall survival (OS) was 18.4 [D] versus 19.2 [DR] months (p=0.33). There were no differences in toxicity., Conclusion: The addition of the third generation bisphosphonate, risedronate, in the setting of effective first line docetaxel based chemotherapy did not increase efficacy, as indicated by the lack of improvement in TTP, OS, PSA- and pain response., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population., Methods: We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery., Results: From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy-surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy-surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003)., Conclusions: Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.).

Background: To achieve T-downstaging and better resectability in locally advanced rectal cancer, neoadjuvant radiochemotherapy (RCT) has become the current standard of treatment. A variety of schemes have been used. This study investigates which scheme had the best effect on these parameters., Methods: Our institution is a referral center for locally advanced rectal cancer. Different neoadjuvant radiochemotherapy regimens were administered: long course radiotherapy (RTH), 5-FU and leucovorin (5FUBolus), a combination of capecitabine and oxaliplatin (CORE), and capecitabine only (CAP). Selection of patients for 1 of the regimens was based on hospital policy rather than patient or tumor characteristics., Results: The data of 504 consecutive patients (n = 181 T3+, n = 323 T4) without metastatic disease (cM0) who underwent surgery for advanced rectal carcinoma between 1994 and 2010 were reviewed. The RTH, 5FUBolus, CORE, and CAP scheme were administered to 106, 137, 155, and 106 patients, respectively. Odds ratios for downstaging were less effective for RTH, 5FUBolus, and CAP (0.31, 0.44, and 0.31; P < .0001) when compared with the CORE scheme. Odds ratios for a R1 resection (3.74, 1.94, 1.14; P = .003) or CRM+ resection (3.78, 2.73, 1.34; P = .001) were also in favor of the CORE. Hazard ratios for CSS were significantly better for the CORE scheme., Conclusions: Downstaging with neoadjuvant treatment results in an increased number of radical resections. In our study, the combination of capecitabine and oxaliplatin appears to be the most effective regimen for locally advanced rectal cancer tumors. However, longer follow-up will be necessary to confirm this conclusion.

Background: In patients with metastatic colorectal cancer (mCRC) with an asymptomatic primary tumor, there is no consensus on the indication for resection of the primary tumor., Methods: A retrospective analysis was performed on the outcome of stage IV colorectal cancer (CRC) patients with or without resection of the primary tumor treated in the phase III CAIRO and CAIRO2 studies. A review of the literature was performed., Results: In the CAIRO and CAIRO2 studies, 258 and 289 patients had undergone a primary tumor resection and 141 and 159 patients had not, respectively. In the CAIRO study, a significantly better median overall survival and progression-free survival was observed for the resection compared to the nonresection group, with 16.7 vs. 11.4 months [P<0.0001, hazard ratio (HR) 0.61], and 6.7 vs. 5.9 months (P=0.004; HR 0.74), respectively. In the CAIRO2 study, median overall survival and progression-free survival were also significantly better for the resection compared to the nonresection group, with 20.7 vs. 13.4 months (P<0.0001; HR 0.65) and 10.5 vs. 7.8 months (P=0.014; HR 0.78), respectively. These differences remained significant in multivariate analyses. Our review identified 22 nonrandomized studies, most of which showed improved survival for mCRC patients who underwent resection of the primary tumor., Conclusions: Our results as well as data from literature indicate that resection of the primary tumor is a prognostic factor for survival in stage IV CRC patients. The potential bias of these results warrants prospective studies on the value of resection of primary tumor in this setting; such studies are currently being planned.

Background: Palliative chemotherapy improves survival in patients with metastasised colorectal cancer. However, there is a lack of data regarding the effectiveness of modern chemotherapy in patients with isolated peritoneal carcinomatosis (PC)., Patients and Methods: All patients with synchronous PC of colorectal origin diagnosed in the Eindhoven Cancer Registry registration area between 1995 and 2008 were included (N = 904). We assessed the use of chemotherapy and overall survival in three time periods related to the availability of different chemotherapy regimens., Results: Chemotherapy use gradually increased over time. Median survival (MS) for patients with PC without other metastases diagnosed in 1995-2000 was 35 weeks [95% confidence interval (CI) 24-43] and 34 weeks (25-54) in 2005-2008. MS in patients diagnosed with PC plus other metastases was 21 weeks (15-27) in 1995-2000 and 26 weeks (18-33) in 2005-2008. In multivariable regression analysis, use of chemotherapy had a beneficial influence on survival only in 2005-2008. In the first two periods, chemotherapy treatment did not decrease the risk for death., Conclusion: Despite increasing usage of palliative chemotherapy and availability of new agents, population-based survival of patients with PC did not improve until very recently. Response to palliative chemotherapy in PC should be evaluated separately from haematogenous metastases.

Background: This population-based study assessed the impact of chemotherapy on general and disease-specific health status of resected colon cancer survivors up to 10 years post-diagnosis., Patients and Methods: Colon cancer survivors diagnosed between 1998 and 2007 were selected from the Eindhoven Cancer Registry. Survivors completed the SF-36 and the EORTC colorectal module (EORTC-QLQ-CR38). Comparisons to a normative population were conducted. Multiple linear regression analyses investigated the association between treatment and health status., Results: Eight hundred and forty eight survivors were evaluated: 29% had chemotherapy (CT); 71% without chemotherapy (nCT). Survivors had similar SF-36 scores and scored better than the normative population on several domains. On the EORTC-QLQ-CR38, male nCT survivors had more sexual problems than CT survivors (p=0.01). Among the sexually active respondents, the survivors reported sex to be less enjoyable than the normative population (p=0.02). In multivariate analyses, CT predicted better physical function, and less male sexual dysfunction and weight loss problems than nCT., Conclusions: Overall, CT survivors have general health status scores comparable to nCT survivors and the normative population up to 10 years since initial diagnosis. Sex-related problems among survivors suggest more attention on this often sensitive issue is required in clinical management., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: In anthracycline-pretreated metastatic breast cancer (MBC) patients, it is unknown whether weekly single-agent docetaxel is preferable to 3-weekly docetaxel regarding its toxicity and efficacy profile., Patients and Methods: In this multicenter, randomised, open-label phase III trial, 162 patients were randomised to weekly docetaxel (group A) or 3-weekly docetaxel (group B). The primary end-point was tolerability; secondary end-points were efficacy and quality of life (QoL)., Results: Group A (weekly docetaxel, n=79) experienced less haematological toxicity, with just 1.3% versus 16.9% febrile neutropenia in group B (3-weekly docetaxel, n=77) (p=0.001). Not this difference, but fatigue and general malaise foremost led to more patient withdrawals in group A (24 versus 12 patients, p=0.032), less patients completing treatment (29 versus 43 patients, p=0.014) and reduced dose-intensity (15.6 versus 26mg/m(2)/week, 58% versus 70% of projected dose, p=0.017). As a result, 3-weekly docetaxel was related to better overall survival in multivariate analysis (hazard ratio 0.70, p=0.036), although in univariate analysis efficacy was similar in both groups. Reported QoL was similar in both groups, but less effective treatment with more general toxicity led to less completed QoL forms in group A (65.4% versus 50%, p=0.049)., Conclusion: Weekly docetaxel is less well tolerated than a 3-weekly schedule, due to more non-haematological toxicity, despite less febrile neutropenia. Also, no efficacy benefits can be demonstrated for weekly docetaxel, which may even be inferior based on multivariate analysis. Therefore, a 3-weekly schedule should be preferred in the setting of MBC., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We analysed population-based treatment and survival data of patients who presented with metastatic rectal cancer. All patients diagnosed with primary synchronous metastatic rectal cancer between 1992 and 2008 in the Eindhoven Cancer Registry area were included. Date of diagnosis was divided into three periods (1992-1999, 2000-2004, 2005-2008) according to the availability of chemotherapy type. We assessed treatment patterns and overall survival according to period of diagnosis. The proportion of patients diagnosed with stage IV disease increased from 16% in 1992-1999 to 20% in 2005-2008 (P < 0.0001). Chemotherapy use increased from 5% in 1992 to 61% in 2008 (P < 0.0001). Resection rates of the primary tumour decreased from 65% in 1992 to 27% in 2008 (P < 0.0001), while metastasectomy rates remained constant since 1999 (9%). Median survival increased from 38 weeks (95% confidence interval (CI) 32-44) in 1992-1999 to 53 weeks (95% CI 48-61) in 2005-2008. Among patients not receiving chemotherapy median survival remained approximately 30 weeks. Multivariable analysis confirmed the lower risk of death among patients diagnosed in more recent years. Increased use of chemotherapy went together with improved median survival among patients with metastatic rectal cancer in the last two decades. Stage migration as an effect of more effective imaging procedures is likely to be partly responsible for this improved survival.

Background: Molecular markers in colon cancer are needed for a more accurate classification and personalized treatment. We determined the effects on clinical outcome of the BRAF mutation, microsatellite instability (MSI) and KRAS mutations in stage II and stage III colon carcinoma., Patients and Methods: Stage II colon carcinoma patients (n = 106) treated with surgery only and 258 stage III patients all adjuvantly treated with 5-fluorouracil chemotherapy were included. KRAS mutations in codons 12 and 13, V600E BRAF mutation and MSI status were determined., Results: Older patients (P < 0.001), right-sided (P = 0.018), better differentiated (P = 0.003) and MSI tumors (P < 0.001) were significantly more frequent in stage II than stage III. In both groups, there was a positive association between mutated BRAF and MSI (P = 0.001) and BRAF mutation and right-sided tumors (P = 0.001). Mutations in BRAF and KRAS were mutually exclusive. In a multivariate survival analysis with pooled stage II and stage III data, BRAF mutation was an independent prognostic factor for overall survival (OS) and cancer-specific survival [hazards ratio (HR) = 0.45, 95% confidence interval (CI) 0.25-0.8 for OS and HR = 0.47, 95% CI 0.22-0.99]. KRAS mutation conferred a poorer disease-free survival (HR = 0.6, 95% CI 0.38-0.97)., Conclusions: The V600E BRAF mutation confers a worse prognosis to stage II and stage III colon cancer patients independently of disease stage and therapy.

Background: The purpose was to assess factors associated with the administration of chemotherapy and their relation to survival at a population-based level., Methods: All patients diagnosed with primary colon cancer stage III from 2001 to 2007 in the area of the Eindhoven Cancer Registry were included (N = 1637). We examined determinants of the administration of adjuvant chemotherapy and their relation to survival., Results: The proportion of patients receiving adjuvant chemotherapy decreased with increasing age from 85% for patients <65 years to 68% for those 65-74 years and 17% for patients > or =75 years, with large interhospital variation. Elderly patients {odds ratio (OR) 0.1 [95% confidence interval (CI) 0.1-0.1]} and those with comorbidity [OR 0.6 (95% CI 0.5-0.8)] received adjuvant chemotherapy less often. Patients with an intermediate [OR 1.4 (95% CI 1.1-1.9)] or high socioeconomic status [OR 1.5 (95% CI 1.1-2.0)] or stage IIIC [OR 1.5 (95% CI 1.1-2.0)] received adjuvant chemotherapy more often. Adjuvant chemotherapy was the most important predictor of survival. In a multivariable analysis, older age was no longer a significant negative predictor of survival, in contrast to comorbidity, higher tumor stage, poor tumor grade, and male gender. The improvement in survival from 2001 to 2006 did not reach statistical significance., Conclusion: Adherence to guidelines for adjuvant chemotherapy was still suboptimal in 2007, especially for elderly patients, and differed widely between hospitals.

Background: Early predictive markers for response are needed for advanced colorectal cancer (ACC) patients. We assessed the value of circulating tumour cells (CTC) in ACC patients treated with chemotherapy plus targeted agents (CAIRO2 phase III trial) and compared the results with computed tomography (CT) imaging., Materials and Methods: CTC were determined at baseline and at different time points during treatment. Patients were stratified into low (less than three CTC per 7.5 ml of blood) or high CTC (three or more CTC per 7.5 ml of blood)., Results: A total of 467 patients were assessable for CTC analysis. Among them, 129 patients (29%) with high baseline CTC had a significantly decreased progression-free survival [PFS; hazard ratio (HR) 1.5] and overall survival (OS; HR 2.2) compared with 322 patients with low baseline CTC. This difference remained statistically significant during treatment. The sensitivity and specificity of high CTC at baseline for the prediction of progressive disease on CT imaging were 16.7% and 70.1%, respectively, and of high CTC at 1-2 weeks after the start of treatment 20.0% and 95.1%, respectively. The combined analysis of CTC and CT imaging provided a more accurate outcome assessment than either modality alone., Conclusions: The CTC count before and during treatment independently predicts PFS and OS in ACC patients treated with chemotherapy plus targeted agents and provides additional information to CT imaging.

Introduction: The use of neo-adjuvant chemotherapy has increased in the treatment of loco-regionally advanced primarily operable breast cancer. As a result of improved neo-adjuvant chemotherapy regimes the number of clinical as well as radiological responses have increased. In case of a complete response it is difficult to identify residual disease and to perform an adequate radical breast-conserving surgery. Therefore localization of the original tumour bed is mandatory. In this study we propose a novel technique with a seed containing radioactive 125 Iodine ((125)I). The (125)I has a half-time of 60 days and is therefore still recognisable with a gamma probe after admittance of several courses of neo-adjuvant chemotherapy., Material and Methods: In the period from July 2003 and November 2008, 47 consecutive patients had successful (125)I seed localization of a breast tumour before starting neo-adjuvant chemotherapy., Results: The overall clinical response rate to neo-adjuvant chemotherapy was 100%. Complete clinical response occurred in 34 patients, partial clinical response occurred in 13 patients. Complete radiological response occurred in 18 patients, partial radiological response occurred in 29 patients. The initial surgical treatment consisted of breast-conserving surgery for all 47 patients, after a mean of 170 days (range: 70-220) after (125)I seed localization. In 19 patients pathology revealed no residual tumour, 23 patients showed a partial response. Only 3 lumpectomies were irradical., Conclusion: This study has shown that (125)I seed localization is a novel and highly successful technique in localizing the tumour bed in patients who receive neo-adjuvant chemotherapy for breast cancer leading to a high percentage of radical margins in case of breast-conserving surgery., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Purpose: Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test., Experimental Design: Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m(2) (group A) or doses based on an equation consisting of midazolam clearance, gamma-glutamyl-transferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course., Results: Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P > 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P > 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was >4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%)., Conclusions: Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment.

Background: Little is known about the longitudinal course of health-related quality of life (HRQoL) in patients with Hodgkin's lymphoma during their post-treatment follow-up and re-adaptation to normal life. We report on the HRQoL of patients treated in the randomised H8 trial of the European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and the Groupe d'Etudes des Lymphomes de l'Adulte (GELA). We aimed to assess HRQoL and fatigue following treatment, to analyse relations with treatment, and to identify factors that predict persistent fatigue., Methods: Patients received HRQoL questionnaires at the end of primary therapy and during follow-up. The EORTC QLQ-C30 was used to assess HRQoL, and the Multidimensional Fatigue Inventory (MFI-20) was used to assess fatigue. Changes of mean HRQoL scores over time were analysed with mixed models. Multiple polytomic nominal logistic regression was done to identify independent baseline predictors of fatigue within MFI-20 dimensions. Analyses were done on an intention-to-treat basis. This study is registered with www.ClinicalTrials.gov, number NCT00379041., Findings: 2666 assessments from 935 patients were analysed. Mean follow-up was 90 months (range 52-118). Age affected all functioning and symptom scores except emotional functioning, with younger age associated with higher functioning and lower severity of symptoms; improvement with time showed similar patterns between age groups. Women reported lower HRQoL and higher symptom scores than did men. Overall, 3.2% (14/439 for role functioning) to 9.7% (43/442 for social functioning) and 5.8% (29/498 for reduced motivation) to 9.9% (49/498 for general fatigue) of patients reported impairments of 10 points or more (on a 0-100 scale) in QLQ-C30 and MFI-20 scores, respectively, independent of age and sex. Emotional domains were more affected than physical ones. There was no relation between HRQoL outcome and type of treatment. Fatigue (MFI-20 scores) at the end of treatment was the only predictive variable for persistent fatigue, with odds ratios varying from 2.58 (95% CI 1.00-6.67) to 41.51 (12.02-143.33; p

Background: The aim of this study was to validate the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based cohort and to study the relevance of revision and extension of the FLIPI., Patients and Methods: Data of 353 unselected patients, 1993-2002, in the Eindhoven Cancer Registry, were collected. Follow-up was completed up to 1 January 2006. Multiple imputations for missing covariates were used. Validity was assessed by comparing observed to predicted survival of the original model and of a revised model with other prognostic variables., Results: The original FLIPI stratified our cohort into three different risk groups based on stage, Hb, lactate dehydrogenase, nodal involvement and age. The discrimination between risk groups was not as good as in the original cohort. A model including age in three categories (< or =60/61-70/>70 years) and presence of cardiovascular disease (CVD) (yes/no) resulted in a better prognostic index. The 5-year overall survival rates were 79%, 59% and 28% in the low-, intermediate- and high-risk groups for the extended FLIPI compared with 81%, 66% and 47% for the original FLIPI, respectively., Conclusions: The performance of the FLIPI was validated in a population-based setting, but could significantly be improved by a more refined coding of age and by including the presence of CVD.

Background and Purpose: The purpose of this study is to analyze the patterns of local recurrence (LR) after intra-operative radiotherapy (IORT) containing multimodality treatment of locally advanced rectal carcinoma (LARC)., Methods and Materials: Two hundred and ninety patients with LARC who underwent multimodality treatment between 1994 and 2006 were studied. For patients who developed LR, the subsite was classified into presacral, postero-lateral, lateral, anterior, anastomotic or perineal. Patient and treatment characteristics were related to subsite of LR., Results: After 5years, 34 patients (13.2%) developed LR. The most prominent subsite of LR was the presacral subsite. 47% of the local recurrences occurred outside the IORT field. Most recurrences developed when IORT was given dorsally, while least occurred when IORT was given ventrally. Especially after dorsal IORT a high amount of infield recurrences were observed (6 of 8; 75%). In multi-variate analysis tumor distance of more than 5cm from the anal verge and a positive circumferential margin were associated with presacral local recurrence., Conclusions: Multimodality treatment is effective in the prevention of local recurrence in LARC. IORT application to the area most at risk is feasible and seems effective in the prevention of local recurrence. Dorsal tumor location results in unfavourable oncologic results.