Bevacizumab for metachronous metastatic colorectal cancer: a reflection of community based practice.

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.

Hospital of diagnosis and likelihood of surgical treatment for pancreatic cancer.

BACKGROUND: Surgical resection for pancreatic cancer offers the only chance of cure. Assessment of the resectability of a pancreatic tumour is therefore of great importance. The aim of the study was to investigate whether centre of diagnosis influences the likelihood of surgery and whether this affects long-term survival. METHODS: Patients diagnosed with non-metastasized pancreatic cancer (M0) between 2005 and 2013 in the Netherlands were selected from the Netherlands Cancer Registry. Hospitals were classified as a pancreatic centre (at least 20 resections/year) or a non-pancreatic centre (fewer than 20 resections/year). The relationship between centre of diagnosis and likelihood of surgery was analysed by multivariable logistic regression. Influence of centre on overall survival was assessed by means of multivariable Cox regression analysis. RESULTS: Some 8141 patients were diagnosed with non-metastasized pancreatic cancer, of whom 3123 (38·4 per cent) underwent surgery. Of the 2712 patients diagnosed in one of 19 pancreatic centres, 52·4 per cent had exploratory laparotomy compared with 31·4 per cent of 5429 patients diagnosed in one of 74 non-pancreatic centres (P < 0·001). A pancreatectomy was performed in 42·8 and 24·6 per cent of the patients respectively (P < 0·001). Multivariable analysis revealed that patients diagnosed in a pancreatic centre had a higher chance of undergoing surgery (odds ratio 2·21, 95 per cent c.i. 1·98 to 2·47). Centre of diagnosis was not associated with improved long-term survival (hazard ratio 0·95, 95 per cent c.i. 0·91 to 1·00). CONCLUSION: Patients with non-metastasized pancreatic cancer had a greater likelihood of having surgical treatment when the diagnosis was established in a pancreatic centre.

Timing of adjuvant chemotherapy and its relation to survival among patients with stage III colon cancer.

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.

Changes in gastrointestinal cancer resection rates.

BACKGROUND: Many developments in medicine are likely to have influenced the treatment of gastrointestinal cancer, including rates of resection. This study sought to investigate changes in surgical resection rates over time among patients with gastrointestinal cancer. METHODS: Patients diagnosed between 1995 and 2012 in the Eindhoven Cancer Registry area were included. Multivariable logistic regression analysis was used to determine the independent influence of interval of diagnosis on the likelihood of having a resection. RESULTS: Among 43,370 patients, crude resection rates decreased between 1995 and 2012 for gastric, colonic and rectal cancer, most notably for patients aged at least 85 years with gastric cancer (from 37.3 to 13.3 per cent), and patients aged 75-84 years and 85 years or more with rectal cancer (from 80.5 to 64.4 per cent, and from 58.9 to 36.0 per cent respectively). After adjustment for patient and tumour characteristics, patients diagnosed between 2008 and 2012 with gastric (odds ratio (OR) 0.71, 95 per cent c.i. 0.55 to 0.92), colonic (OR 0.52, 0.44 to 0.62), rectal (OR 0.39, 0.33 to 0.48) and periampullary (OR 0.42, 0.27 to 0.66) cancers were less likely to undergo resection than those diagnosed between 1995 and 1998. Patients diagnosed with pancreatic cancer were more likely to undergo resection in recent periods (OR 4.13, 2.57 to 6.64). CONCLUSION: Resection rates have fallen over time for several gastrointestinal cancers. This might reflect increased availability of other treatments, better selection of patients as a result of improved diagnostic accuracy, risk-avoiding behaviour and transparency related to surgical outcomes at hospital and surgeon level.

Trends in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of synchronous peritoneal carcinomatosis of colorectal origin in the Netherlands.

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.

Peritoneal carcinomatosis is less frequently diagnosed during laparoscopic surgery compared to open surgery in patients with colorectal cancer.

BACKGROUND: During resection of a colorectal tumor a careful inspection of the abdomen should be performed to detect metastases. The aim of the current study was to compare the proportions of patients diagnosed with peritoneal carcinomatosis (PC) during laparoscopic resection (LR) and open resection (OR). METHODS: All patients who underwent resection for colorectal cancer in the Eindhoven Cancer Registry area between 2008 and 2012 were included. Proportions of patients with PC were compared between surgical techniques. Multivariate logistic regression analysis was performed. RESULTS: 6687 Patients underwent resection for colorectal cancer, of whom 1631 patients (24%) underwent LR, 4665 patients (70%) underwent OR. Conversion took place in 391 patients (19% of laparoscopic treated patients). PC was diagnosed in 1.4% of patients undergoing LR, in 5.0% of patients undergoing OR, and in 3.3% of patients in whom LR was converted to OR (p < 0.001). After adjustment for patient and tumor characteristics (e.g., T- and N-stage), patients who were treated by LR had a lower chance to be diagnosed with PC during surgery than patients undergoing OR (odds ratio = 0.42, p < 0.001). CONCLUSIONS: Patients undergoing surgery for colorectal cancer are less frequently diagnosed with PC during LR in comparison to OR. Since effective treatment is currently available for selected patients with PC, a thorough inspection of the peritoneum during surgery is of paramount importance to offer these patients a chance for long-term survival and even cure.

Metachronous peritoneal carcinomatosis after curative treatment of colorectal cancer.

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.

The standardised mortality ratio is unreliable for assessing quality of care in rectal cancer.

BACKGROUND: The standardised mortality ratio (SMR) for rectal or anal cancer was above average in a large tertiary referral centre for locally advanced rectal cancer in the Netherlands. The aim of this study was to investigate whether the increased SMR was indeed related to poor quality of care or whether it could be explained by inadequate adjustment for case-mix factors. METHODS: Between 2006 and 2008, 381 patients were admitted for rectal or anal cancer. The SMR score of this diagnostic group was 230 (95% CI 140 to 355), corresponding with 20 in-hospital deaths. The hospital dataset was merged with data from the Eindhoven Cancer Registry to obtain more detailed information. RESULTS: Patients admitted for palliative care only accounted for 45% (9/20) of the in-hospital mortality. In contrast to the high SMR, postoperative mortality was low, i.e. 2.6%. The majority of the rectal or anal cancer patients were diagnosed in and referred from another hospital. Referred patients more often had an advanced tumour stage, more often underwent resection and were more frequently treated with chemotherapy and/or radiotherapy than non-referred patients (p<0.01). Postoperative mortality rates for referred and non-referred patients were 2.9% and 1.9%, respectively. CONCLUSIONS: The increased SMR appeared to be caused by the admission of patients who received palliative care only. Consequently, the SMR is unreliable for the assessment of quality of care in patients with rectal or anal cancer.

Smoking cessation has no influence on quality of life in patients with peripheral arterial disease 5 years post-vascular surgery.

OBJECTIVES: Smoking is an important modifiable risk factor in patients with peripheral arterial disease (PAD). We investigated differences in quality of life (QoL) between patients who quitted smoking during follow-up and persistent smokers. DESIGN: Cohort study. METHODS: Data of 711 consecutively enrolled patients undergoing vascular surgery were collected in 11 hospitals in the Netherlands. Smoking status was obtained at baseline and at 3-year follow-up. A 5-year follow-up to measure QoL was performed with the EuroQol-5D (EQ-5D) and Peripheral Arterial Questionnaire (PAQ). RESULTS: After adjusting for clinical risk factors, patients, who quit smoking within 3 years after vascular surgery, did not report an impaired QoL (EQ-5D: odds ratio (OR) = 0.63, 95% confidence interval (CI) = 0.28-1.43; PAQ: OR = 0.76, 95% CI = 0.35-1.65; visual analogue scale (VAS): OR = 0.88, 95% CI = 0.42-1.84) compared with patients, who continued smoking. Current smokers were significantly more likely to have an impaired QoL (EQ-5D: OR = 1.86, 95% CI = 1.09-3.17; PAQ: OR = 1.63, 95% CI = 1.00-2.65), although no differences in VAS scores were found (OR = 1.17, 95% CI = 0.72-1.90). CONCLUSIONS: There was no effect of smoking cessation on QoL in PAD patients undergoing vascular surgery. Nevertheless, given the link between smoking, complications and mortality in this patient group, smoking cessation should be a primary target in secondary prevention.

COPD and cancer mortality: the influence of statins.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of lung cancer, independently of smoking. However, the relationship between COPD and total cancer mortality is less certain. A study was undertaken to investigate the association between COPD and total cancer mortality and to determine whether the use of statins, which have been associated with cancer risk in other settings, modified this relationship. METHODS: The study included 3371 patients with peripheral arterial disease who underwent vascular surgery between 1990 and 2006; 1310 (39%) had COPD and the rest did not. The primary end point was cancer mortality (lung and extrapulmonary) over a median follow-up of 5 years. RESULTS: COPD was associated with an increased risk of both lung cancer mortality (hazard ratio (HR) 2.06; 95% CI 1.32 to 3.20) and extrapulmonary cancer mortality (HR 1.43; 95% CI 1.06 to 1.94). The excess risk was mostly driven by patients with moderate and severe COPD. There was a trend towards a lower risk of cancer mortality among patients with COPD who used statins compared with patients with COPD who did not use statins (HR 0.57; 95% CI 0.32 to 1.01). Interestingly, the risk of extrapulmonary cancer mortality was lower among statin users with COPD (HR 0.49; 95% CI 0.24 to 0.99). CONCLUSIONS: COPD was associated with increased lung and extrapulmonary cancer mortality in this large cohort of patients with peripheral arterial disease undergoing vascular surgery. The risk of lung cancer mortality increased with progression of COPD. Statins were associated with a reduced risk of extrapulmonary cancer mortality in patients with COPD.

The prognostic value of impaired walking distance on long-term outcome in patients with known or suspected peripheral arterial disease.

OBJECTIVES: To assess the predictive value of walking distance after an exercise test on long-term outcome in patients with normal and impaired ankle-brachial index (ABI). DESIGN: A total of 2191 patients with known or suspected peripheral arterial disease (PAD), who were referred for a single-stage treadmill exercise test to diagnose or evaluate their PAD, were enrolled in an observational study between 1993 and 2006. MATERIALS AND METHODS: They were divided into two groups: normal ABI (>or=0.90) and impaired ABI (<0.90). Walking distance was divided into quartiles (no (reference), mild, moderate or severe impairment). RESULTS: In patients with normal ABI, severe walking distance was, after adjustment, associated with higher mortality risk (hazard ratio (HR): 2.60 (range: 1.16-5.78)). In patients with impaired ABI, all walking distance impairment quartiles were associated with higher mortality (mild HR: 1.26 (range: 0.95-1.67), moderate HR: 1.52 (range: 1.13-2.05) and severe HR: 1.69 (range: 1.26-2.27)). Furthermore, comparable associations were observed between all walking distance quartiles, cardiac death or major adverse cerebrovascular and cardiac events. CONCLUSIONS: Our study illustrated that walking impairment is a strong prognostic indicator of long-term outcome in patients with impaired and normal ABI, which should be a warning sign to physicians to monitor these patients carefully and to provide them optimal treatment.

Methionine loading does not enhance the predictive value of homocysteine serum testing for all-cause mortality or major adverse cardiac events.

BACKGROUND: Hyperhomocysteinaemia is independently associated with atherosclerotic disease. Methionine loading could improve the predictive value of hyperhomocysteinaemia by detecting mild disturbances in enzyme activity. The aims of this study were to determine the beneficial effect of methionine loading on the predictive value of homocysteine testing for long-term mortality and major adverse cardiac events (MACE). METHODS: In an observational study, 1122 patients with suspected or known vascular disease, underwent homocysteine testing, which was measured fasting and again 6 h after methionine loading. Hyperhomocysteinaemia was defined as a fasting level > or =15 micromol/L and post-methionine loading level > or =45 micromol/L or an increase of > or =30 micromol/L above fasting levels. Primary end-points were death and MACE. Multivariate Cox regression analysis was used, adjusting for all cardiac risk factors. RESULTS: During follow up (mean 8.9 +/- 3.4 years), 98 patients died (8.7%), 86 had a MACE (7.7%), 579 patients had normal tests, 134 patients had only fasting hyperhomocysteinaemia, 226 only post-methionine hyperhomocysteinaemia and 183 patients had both. In multivariate analysis, overall survival and MACE-free survival were significantly worse for those with fasting hyperhomocysteinaemia, with hazard ratios of 1.86 (95% confidence interval (CI) 1.20-2.87) and 2.24 (95%CI 1.41-3.53), respectively. The addition of hyperhomocysteinaemia after methionine loading did not significantly increase the risk of death or MACE, with hazard ratios of 0.97 (95%CI 0.52-1.81) and 0.89 (95%CI 0.47-1.69), respectively. CONCLUSION: The presence of post-methionine hyperhomocysteinaemia did not significantly alter risk of death or MACE in patients with normal or increased fasting homocysteine levels, respectively. In conclusion, methionine loading does not improve the predictive value of homocysteine testing with regard to long-term mortality or MACE.

Beta-blockers improve outcomes in kidney disease patients having noncardiac vascular surgery.

Beta-blockers are known to improve postoperative outcome after major vascular surgery. We studied the effects of beta-blockers in 2126 vascular surgery patients with and without kidney disease followed for 14 years. Creatinine clearance was calculated using the Cockcroft-Gault equation, and kidney function was categorized as Stage 1 for a reference group of 550 patients, Stage 2 with 808 patients, Stage 3 with 627 patients, and combined Stages 4 and 5 with 141 patients. Outcome measures were 30-day and long-term all-cause mortality with a mean follow-up of 6 years. Cox proportional hazards models were used to control cardiovascular risk factors, including propensity for beta-blocker use. In all, 129 (6%) and 1190 (56%) patients died respectively. Mortality rates were three- and two-fold higher, respectively, for patients at Stages 3-5 compared to the reference group for the two outcomes. beta-Blocker use was significantly associated with a lower risk of mortality after surgery. The overall adjusted hazard ratio was 0.35 and 0.62, respectively, for individuals at Stages 3-5 compared to the reference group for 30-day and long-term mortality. This study shows that kidney function is a predictor of all-cause mortality and beta-blocker use is associated with a lower risk of death in kidney disease patients undergoing elective vascular surgery.

The influence of aging on the prognostic value of the revised cardiac risk index for postoperative cardiac complications in vascular surgery patients.

OBJECTIVE: The Lee-risk index [Lee-index] was developed to predict major adverse cardiac events [MACE]. However, age is not included as a risk factor. The aim was to assess the value of the Lee-index in vascular surgery patients among different age categories. METHODS: Of 2642 patients cardiovascular risk factors were noted to calculate the Lee-index. Patients were divided into four age categories; < or = 55 (n=396), 56-65 (n=650), 66-75 (n=1058) and > 75 years (n=538). Outcome measures were postoperative MACE (cardiac death, MI, coronary revascularization and heart failure). The performance of the Lee-index was determined using C-statistics within the four age groups. RESULTS: The incidence of MACE was 10.9%, for Lee-index 1, 2 and > or = 3; 6%, 13% and 20%, respectively. However, the prognostic value differed among age groups. The predictive value for MACE was highest among patients under 55 year (0.76 vs 0.62 of patients aged > 75). The prediction of MACE improved in elderly (aged > 75) after adjusting the Lee-index with age, revised risk of operation (low, low-intermediate, high-intermediate and high-risk procedures) and hypertension (0.62 to 0.69). CONCLUSION: The prognostic value of the Lee-index is reduced in elderly vascular surgery patients, adjustment with age, risk of surgical procedure, and hypertension improves the Lee-index significantly.

A comparison of quality of life, disease impact and risk perception in women with invasive breast cancer and ductal carcinoma in situ.

We compared the health-related quality of life, impact of the disease, risk perception of recurrence and dying of breast cancer, and understanding of diagnosis of patients with ductal carcinoma in situ (DCIS) and invasive breast cancer 2-3 years after treatment. We included all women (N=211) diagnosed with DCIS or invasive breast cancer TNM stage I (T1, N0, and M0) in three community hospitals in the southern part of The Netherlands in the period 2002-2003. After verifying the medical files, 180 disease free patients proved eligible for study entry, 47 of whom had DCIS and 133 stage I invasive breast cancer. One-hundred and thirty-five patients returned a completed questionnaire (75% response). No significant differences were found between women with DCIS and invasive breast cancer on the physical and mental component scale of the RAND SF-36, nor on the WHO-5, which assesses well-being. In contrast, women with DCIS reportedly had a better physical health, better sex life and better relationships with friends/acquaintances than women with invasive breast cancer. Despite their better prognosis, the DCIS-group had comparable perceptions of the risk of recurrence and dying of breast cancer as women with invasive breast cancer. However, this did not appear to affect their well-being significantly.