Survival benefit of statins in older patients with rectal cancer: A Swedish population-based cohort study.

OBJECTIVES: Increasing evidence suggests that statins may have antitumor effects but their role in rectal cancer appears inconclusive. The aim of this study was to investigate whether statins may have an impact on survival of older and younger patients with rectal cancer. MATERIALS AND METHODS: This study included 238 patients ≥70 years and 227 patients <70 years old, from the Southeast Health Care Region of Sweden, who were diagnosed with rectal adenocarcinoma between 2004 and 2013. RESULTS: In the older group (n = 238), statin use at the time of diagnosis was related to better cancer-specific survival (CSS) and overall survival (OS), compared to non-use (CSS: Hazard Ratio (HR), 0.37; 95% CI, 0.19-0.72; P = .003; OS: HR, 0.62; 95% CI, 0.39-0.96; P = .032). In the older group with stages I-III disease (n = 199), statin use was associated with better disease-free survival (DFS) compared to non use (HR, 0.18; 95% CI, 0.06-0.59; P = .005). The improvement of CSS, OS and DFS remained significant after adjusting for potential confounders. In the older group with stage III disease, statin users had better CSS and DFS compared to non-users (log rank P = .043; log-rank P = .028, respectively). In the older group with short course radiotherapy, statin use was related to better CSS (log-rank P = .032). No such association was present in the younger group. CONCLUSION: Statin use was related to improved survival in older patients with rectal cancer. This observation is important given the low cost and safety of statins as a drug.

From palliative to curative treatment - stage IV mucinous adenocarcinoma, successfully treated with metronomic capecitabine in combination with Bevacizumab and surgery- a case report.

BACKGROUND: Mucinous adenocarcinoma (MAC) represents 6-19 % of all colorectal carcinoma. It is associated with poorer response to chemotherapy and chemoradiotherapy. CASE PRESENTATION: A 27-year-old Swedish woman presented with stomach pain and weight loss, and was diagnosed with locally advanced MAC in the transverse colon as well as 3 liver metastases. Neoadjuvant treatment with fluorouracil, folinic acid and oxaliplatin (FLOX) failed due to several infections, pulmonary embolism and deteriorated performance status. The patient was therefore considered palliative. Palliative treatment with metronomic capecitabine 500 mg × 2 daily and bevacizumab every other week were initiated. After 4 months of treatment the tumors had regressed and the patient was able to undergo radical surgery, thereby changing the treatment intention from palliative to curative. No adjuvant chemotherapy was given. There were no signs of recurrence 9 months later. CONCLUSIONS: The role of the combination of metronomic capecitabine and bevacizumab in patients with MAC merits further investigation.

Efficacy of surgery and adjuvant therapy in older patients with colorectal cancer: a STROBE-compliant article.

The present study aimed to assess the efficacy of surgery and adjuvant therapy in older patients (age≥70 years) with colorectal cancer (CRC). Older CRC patients are under-represented in available clinical trials, and therefore their outcomes after receiving surgery and adjuvant therapy are unclear. From two prospective Swedish databases, we assessed a cohort of 1021 patients who underwent curative surgery for stage I, II, or III primary CRC, with or without adjuvant chemotherapy/radiotherapy. Of the patients with colon cancer (n=467), 182 (39%) were aged <70 years, 162 (35%) aged 70 to 80 years, and 123 (26%) were aged ≥80 years. Of rectal cancer patients (n=554), 264 (48%) were aged <70 years, 234 (42%) aged 70 to 80 years, and 56 (10%) aged ≥80 years. Older patients with either colon or rectal cancer had higher comorbidity than did younger patients. Older patients with colon cancer had equivalent postoperative morbidity and 30-day mortality to younger patients. Rectal cancer patients aged ≥80 years had a higher 30-day mortality than younger patients (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.6-4.55; P=0.03). For either colon or rectal cancer, adjuvant chemotherapy compromised the 5-year overall survival (OS) of older patients with stage II disease and had no effect on those with stage III disease. Receiving adjuvant chemotherapy was a poor factor of OS for older patients with either colon (HR 1.88, 95% CI: 1.20-4.35, P=0.03) or rectal cancer (HR 1.72, 95% CI: 1.05-2.26, P=0.004). Preoperative short-course radiotherapy improved both OS and local control for older patients with stage III rectal cancer and had no effect on those with stage II disease. Radiotherapy was a favorable factor for the OS of the older patients with rectal cancer (HR 0.42, 95% CI: 0.21-3.57, P=0.01). In conclusion, Older CRC patients had equal safety of surgery as younger patients, except rectal cancer patients aged ≥80 years that had a higher mortality. Adjuvant 5FU-based chemotherapy did not benefit older CRC patient, while neoadjuvant radiotherapy improved the prognosis of older patients with stage III rectal cancer.

SPARCL1 expression increases with preoperative radiation therapy and predicts better survival in rectal cancer patients.

PURPOSE: The secreted protein acidic and rich in cysteine-like 1 (SPARCL1) is expressed in various normal tissues and many types of cancers. The function of SPARCL1 and its relationship to a patient's prognosis have been studied, whereas its relationship to radiation therapy (RT) is not known. Our aim was to investigate the expression of SPARCL1 in rectal cancer patients who participated in a clinical trial of preoperative RT. METHODS AND MATERIALS: The study included 136 rectal cancer patients who were randomized to undergo preoperative RT and surgery (n=63) or surgery alone (n=73). The expression levels of SPARCL1 in normal mucosa (n=29), primary tumor (n=136), and lymph node metastasis (n=35) were determined by immunohistochemistry. RESULTS: Tumors with RT had stronger SPARCL1 expression than tumors without RT (P=.003). In the RT group, strong SPARCL1 expression was related to better survival than weak expression in patients with stage III tumors, independent of sex, age, differentiation, and margin status (P=.022; RR = 18.128; 95% confidence interval, 1.512-217.413). No such relationship was found in the non-RT group (P=.224). Further analysis of interactions among SPARCL1 expression, RT, and survival showed statistical significance (P=.024). In patients with metastases who received RT, strong SPARCL1 expression was related to better survival compared to weak expression (P=.041) but not in the non-RT group (P=.569). CONCLUSIONS: SPARCL1 expression increases with RT and is related to better prognosis in rectal cancer patients with RT but not in patients without RT. This result may help us to select the patients best suited for preoperative RT.

Low-dose capecitabine (Xeloda) for treatment for gastrointestinal cancer.

The prodrug capecitabine (Xeloda) has been an important drug for treatment for gastrointestinal cancer (GI-cancer). This study explores the efficacy of continuous metronomic Xeloda, as well as tolerability and best response during treatment. Patients (n=35) with stage IV GI-cancer were included in the study and were divided into two groups; upper (n=13) and lower (n=22) GI-cancer. All patients were given continuous metronomic Xeloda (500 mg×2). Best response was measured by radiological and clinical examination including laboratory results. Standard RECIST criteria were used. Median age was 66 (range 29-86). Those patients who received first and second line had the longest duration of treatment. For patients with metastatic gastrointestinal cancer, metronomic capecitabine (Xeloda) may be beneficial both as far as tumor control and quality of life is concerned. In this pilot study, palliation for more than 2 years is observed for 6 of the 35 patients.

A clinical study of metastasized rectal cancer treatment: assessing a multimodal approach.

Metastasized rectal cancer has long been considered incurable. During recent years, the treatment of rectal cancer patients has been improved, and nowadays, a subgroup of patients might even be cured. The aim of this study was to investigate the optimal timing of treatment in a multimodal therapy schedule in order to see whether the addition of bevacizumab (Avastin) to conventional chemotherapy was effective. The study included 39 patients with metastatic rectal cancer between 2009 and 2011, and three were excluded due to the lack of metastases or lack of follow-up information. The remaining 36 patients were divided into groups by treatment intention. The group with curative intention received mainly oxaliplatin (Eloxatin) in combination with capecitabine (Xeloda) with or without bevacizumab (Avastin) for 2 months followed by preoperative radiotherapy (RT) and surgery. Palliative patients had very different treatments depending on their needs of palliation. The median survival time for patients with curative intention was 31 months and for the palliative patients 12 months. Four of the patients (11%) with curative intention were considered cured at the end of follow-up. The response to chemotherapy after 2-month treatment is a good prognostic sign for which patients can be cured. Long-lasting palliation can be obtained with this treatment schedule. The main side effects were gastrointestinal events, including bowel perforation, neuropathy, thrombo-embolic disease and reduced general condition. All side effects are known, and the treatment is considered tolerable. We conclude that a good treatment schedule would be oxaliplatin (Eloxatin) in combination with capecitabine (Xeloda) with or without bevacizumab (Avastin) for 2 months, followed by preoperative RT and surgery.

Cognitive, psychosocial, somatic and treatment factors predicting return to work after breast cancer treatment.

BACKGROUND: Breast cancer (BC) may affect the ability to work. In this study, we want to identify any associations between cognitive, psychosocial, somatic and treatment factors with time to return to work (RTW) among women treated for BC. METHODS AND PARTICIPANTS: At eight (baseline) and 11(follow-up) months after BC diagnosis, women who had received adjuvant treatment for early BC at Stockholm South General Hospital completed the Headminder neuropsychological tests to obtain the Cognitive Stability Index (CSI), the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and its Breast Cancer Module. At both time points, we compared the scores from women who had returned to work with those who had not. We also reviewed the medical certificates of women still on sick leave at 8, 11 and 18 months after diagnosis to determine why they had not returned to work. RESULTS: At baseline, 29 of 45 enroled women were working and 15 were not (one dropped out after baseline testing). The 14 women still not working 11 months after BC diagnosis had more advanced BC (OR = 3.64, 95% CI 2.01-7.31), lymph-node involvement (OR = 18.80, 95% CI 5.32-90.69) and Her 2-positive tumours (OR = 10.42,95% CI 2.19-65.32) than did working women. None of the scores for the four cognitive domains changed significantly at follow-up in either group. Comments on the medical certificates generally supported these findings. Independently of any adjuvant cancer therapy, overall quality of life improved and most women did RTW 18 months after BC diagnosis. CONCLUSIONS: Chemotherapy is associated with longer periods of sick leave. Cognitive functions do not predict RTW. Independently of any adjuvant therapy, most women eventually RTW in a few months. The ability to predict RTW after BC treatment should help prepare higher-risk patients for delayed RTW and allow earlier interventions to restore their social relations and quality of life.

Effects of adjuvant treatment on cognitive function in women with early breast cancer.

PURPOSE: Whether adjuvant therapy impairs cognitive function in women with breast cancer (BC) is unclear. We determined the effects of adjuvant therapy on cognitive function in women with early BC. METHODS: We consecutively and prospectively enrolled women aged 40-69 years who had a positive radiographic finding from the mammography screening program at Stockholm South General Hospital. All women completed the Headminder Web-based neuropsychological battery Cognitive Stability Index (CSI) for response speed, processing speed, memory, and attention before diagnosis (T1), after surgery and before adjuvant treatment (T2), 6 months after start of adjuvant treatment (T3), and after another 3 months of follow-up (T4). Women with BC were divided into those receiving chemotherapy, hormone therapy, or no adjuvant medical therapy. Women without a diagnosis of BC served as healthy controls. RESULTS: Of the 146 women enrolled, 77 had BC of whom 18 received chemotherapy; 45, hormone therapy, and 14, no adjuvant medical therapy; 69 were healthy controls. Memory scores for women with BC were significantly lower than those for controls over time, even after controlling for age and education. Memory and response speed scores were lower after chemotherapy than before (P<0.01 for both). Processing speed and attention improved significantly over time in all groups, a result consistent with a practice effect. CONCLUSION: Our results indicate subtle changes related to time course and treatment. Especially, that chemotherapy may impair memory and response speed in women with BC, consistent with those reported by BC survivors after adjuvant medical treatment.

The effects of breast cancer diagnosis and surgery on cognitive functions.

BACKGROUND: Women with breast cancer (BC) report cognitive impairment. Receiving a BC diagnosis may have a negative psychological impact. We sought to determine whether a diagnosis of BC and subsequent surgical treatment reduced cognitive function. MATERIAL AND METHODS: We recruited women, who had a positive radiographic finding, consecutively from the mammography screening program at Stockholm South General Hospital. All subjects completed the Headminder Web-based neuropsychological battery Cognitive Stability Index (CSI) for response speed, processing speed, memory, and attention at enrolment (T1, Baseline). CSI was administered again, after BC was ruled out, or after sector resection or mastectomy, if BC was confirmed by cytology or biopsy (T2, Retest). RESULTS AND CONCLUSION: Of the 148 women approached, 146 were enrolled; 69 were healthy and 77 had BC. Comparison between groups at baseline, according to independent t-test, showed significant differences in response speed and processing speed. Cognitive abilities did not decline in either group on any of the measured domains. Our results suggest that a diagnosis of BC and subsequent surgery is not associated with substantial cognitive decline at retest. However, the lack of improvement in attention at retest among BC patients may be suggestive of a decline.

Erythropoietin therapy and cancer related anaemia: updated Swedish recommendations.

Due to concerns related to treatment with erythropoietin (EPO) and possible negative effects on tumour control, a workshop was organised by the Medical Products Agency of Sweden with the aim to revise national treatment guidelines if needed. In patients with solid tumours, conflicting results have been reported with respect to tumour control and survival. Until further notice it is therefore recommended that EPO should be used restrictively in the treatment of patients with cancer and that the anticipated improvement in quality of life should be evaluated against potential risks.

Incidence of carcinoma of the oesophagus and gastric cardia. Changes over time and geographical differences.

BACKGROUND: The incidence of adenocarcinoma of the oesophagus is rising in many western countries including Sweden. METHODS: We have studied the latest data concerning this as well as trends in the incidence of squamous cell carcinoma and adenocarcinoma of gastric cardia. Data was extracted from the Swedish cancer registry and analyzed regarding gender, age, region, histology and location of tumour. RESULTS: The results show an increasing incidence of adenocarcinoma in both oesophagus and gastric cardia. Squamous cell carcinomas show a more stable development with a slight decrease of incidence. Adenocarcinoma is now the most common histological type of cancer in the oesophageal/cardia region in Sweden. Results also suggest a possible drift in location of adenocarcinoma from gastric cardia towards oesophagus. Overall a higher incidence was found in the male population and no trends in patient age at onset could be found. Squamous cell carcinoma is still slightly more common in urban regions.

Current state of adjuvant therapy in resected pancreatic adenocarcinoma.

Pancreatic carcinoma cannot generally be cured by surgery alone. This review summarizes the development of adjuvant therapy over the past two decades. Four randomized controlled trials compare long-term survival of different treatments. The small GITSG-study supports combined chemoradiation, but the EORTC-study found no significant effect. A Norwegian study of adjuvant chemotherapy found an increased median survival, but no effect beyond two years. The large ESPAC-1 study shows a benefit for 5-FU based chemotherapy, while chemoradiation had a negative effect. Thus, evidence favours adjuvant therapy, but 5-FU may not be the ultimate drug. Support for gemcitabine is given by preliminary data from a German randomized trial, and further American and European studies are upcoming. However, postoperative therapy is problematic, as 20-30% of resected patients never undergo treatment because of slow recovery or other reasons. Preoperative therapy has some theoretical advantages, and moreover, patients with rapidly progressive disease may be spared surgery. Randomized controlled trials are lacking, but published results compare well with postoperative, adjuvant therapy. The value of locally targeted therapy is difficult to assess. Reasonable results have been obtained with regional chemotherapy, whereas intraoperative radiotherapy does not seem to increase survival despite reducing reducing local recurrences.

Adjuvant chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group.

Due to uncertainties regarding clinically meaningful gains from adjuvant chemotherapy after colorectal cancer surgery, several Nordic Groups in the early 1990s initiated randomised trials to prove or reject such gains. This report gives the joint analyses after a minimum 5-year follow-up. Between October 1991 and December 1997, 2 224 patients under 76 years of age with colorectal cancer stages II and III were randomised to surgery alone (n = 1 121) or adjuvant chemotherapy (n = 1 103) which varied between trials (5FU/levamisole for 12 months, n = 444; 5FU/leucovorin for 4-5 months according to either a modified Mayo Clinic schedule (n = 262) or the Nordic schedule (n = 397). Some centres also randomised patients treated with 5FU/leucovorin to+/-levamisole). A total of 812 patients had colon cancer stage II, 708 colon cancer stage III, 323 rectal cancer stage II and 368 rectal cancer stage III. All analyses were according to intention-to-treat. No statistically significant difference in overall survival, stratified for country or region, could be found in any group of patients according to stage or site. In colon cancer stage III, an absolute difference of 7% (p = 0.15), favouring chemotherapy, was seen. The present analyses corroborate a small but clinically meaningful survival gain from adjuvant chemotherapy in colon cancer stage III, but not in the other presentations.

Upper extremity deep venous thrombosis in patients with 5-fluorouracil-containing adjuvant chemotherapy--three case reports and a review.

Catheter-related deep venous thrombosis is a complication that can occur in patients receiving chemotherapy. Three such cases are described and a review of the literature is made, focusing on recent results regarding possible thrombogenic mechanisms and the high prevalence of non-symptomatic thrombosis as well as the high morbidity and mortality associated with upper extremity deep venous thrombosis. Special emphasis is given to the cytotoxic effects of 5-fluorouracil on vascular endothelium and the likely link to thrombotic complications. The possible differences between two different methods of administering chemotherapy, continuous infusion and bolus dose administration, in this regard are briefly discussed. It is concluded that the first steps towards an understanding of the mechanisms behind the vascular effects of 5-fluorouracil have been taken. Much remains to be done before active interaction with the pathogenic processes leading to vascular and cardiac complications can be realized, yet various forms of anticoagulant therapy could well be an efficient form of prophylaxis.

A systematic overview of radiation therapy effects in oesophageal cancer.

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for oesophageal cancer is based on data from 42 randomized trials and 2 meta-analyses. A total of 44 scientific articles are included, involving 5 772 patients. The conclusions reached can be summarized as follows: There is fairly strong evidence that preoperative radiotherapy does not improve the survival in patients with potentially resectable oesophageal cancer. There is moderate evidence that preoperative chemo-radiotherapy has no beneficial impact on the survival of patients with potentially resectable oesophageal cancer. There is no scientific evidence that postoperative radiotherapy improves survival in patients with resectable oesophageal cancer. The documentation is, however, poor, consisting of only three randomized trials. There is fairly strong evidence that concomitant (but not sequential) chemo-radiotherapy gives significantly better survival rate than radiotherapy alone in inoperable oesophageal cancer. The results of the reported clinical trials are, however, conflicting, and no solid conclusion can be drawn. Hyperfractionated radiotherapy has been compared with conventionally fractionated radiotherapy in two randomized studies with conflicting results and no firm conclusion can be drawn.

Effects of probucol on endothelial damage by 5-fluorouracil.

Cardiotoxicity is a serious side effect of cancer treatment with the commonly used drug 5-fluorouracil (5-FU). The pathophysiology of this is unclear. Experimental studies show a thrombogenic effect of 5-FU, secondary to a direct toxic effect on the endothelium, possibly mediated by radical generation. Probucol is a lipid-lowering drug with strong antioxidant properties. The aim of this study was to evaluate the possibility of using probucol treatment to protect against the toxicity of 5-FU on vascular endothelium of the central artery in the ears of rabbits. Five groups of rabbits were treated with 1) 5-FU, 2) saline, 3) probucol high-dose and saline, 4) probucol high-dose and 5-FU, 5) probucol low-dose and 5-FU. Damage to the arterial endothelium was evaluated by scanning electron microscopy. Damage to the endothelium in 5-FU + probucol-treated animals was minimal and comparable to that of the control group. Intima disruption or thrombus formation was seen with 5-FU only. The results of the study indicate that treatment with probucol prevents 5-FU-induced endothelial injury.

Endothelial damage after treatment with low-molecular weight heparins--a morphological study.

OBJECTIVE: Recent studies failed to show long-term benefit with low-molecular weight heparins (LMWH) in unstable coronary heart disease. A previous study of vascular effects of the cytostatic agent 5-fluorouracil (5-FU) showed that dalteparin prevented thrombosis induced by 5-FU but endothelial damage was not ameliorated and was present also in animals treated with dalteparin only. This study investigates the influence of LMWH currently in clinical use on arterial endothelium in vivo. DESIGN: Eighty rabbits in four groups were treated with dalteparin, enoxaparin, tinzaparin and saline, respectively. Arterial endothelium was examined after 3, 14, 30 and 60 days with scanning electron microscopy. RESULTS: All three groups treated with LMWH showed moderate damage to the endothelium, with contracted vessel wall and endothelial cells, cell membrane damage, denudation of subendothelium and adhering platelets. Contrarily, the control group exhibited a normal endothelium. CONCLUSION: Morphologic examination of arterial endothelium shows that all investigated LMWH exert a moderate toxic effect on endothelial cells. The clinical impact of these observations, e.g. concerning effect of long-term LMWH treatment, needs to be further elucidated.

Chemoradiotherapy of esophageal cancer.

Esophageal cancer is a disease with a poor prognosis and high biological aggressiveness. The disease used to be considered a mainly local problem, and palliative care with relief of dysphagia was the goal for most of those concerned with the disease. When surgical techniques were improved and parallel progress was made in intensive care and postoperative care, some patients could be cured of the disease. The development of pre- or postoperative radiotherapy also improved local control. Partly because of the interest that began to be focused on improving survival for this diagnostic group, chemotherapy combined with radiotherapy has been incorporated into the therapeutic arsenal. The aim of this review is to shed light on current treatment principles for esophageal cancer. However, treatment results from studies utilizing combination chemotherapy given concurrently with radiotherapy support the conclusion that well-designed randomized trials with long-term follow-ups should be performed.