A clinical risk score to predict 3-, 5- and 10-year survival in patients undergoing surgery for Dukes B colorectal cancer.

BACKGROUND: The prognosis of patients with Dukes stage B colorectal cancer is unpredictable and there is continuing interest in simply and reliably identifying patients at high risk of developing recurrence and dying of their disease. The aim of this study was to devise a clinical risk score to predict 3-, 5- and 10-year survival in patients undergoing surgery for Dukes stage B colorectal cancer. METHODS: A total of 1350 patients who underwent surgery for Dukes stage B colorectal cancer between 1991 and 1994 in 11 hospitals in Scotland were included in the analysis. RESULTS: On follow-up, 926 patients died of whom 479 died of their cancer. At 10 years, cancer-specific survival was 61% and overall survival was 38%. On multivariate analysis, age ≥75 (hazard ratio (HR) 1.45, 95% confidence interval (CI) 1.15-1.82, P=0.001), emergency presentation (HR 1.59, 95% CI 1.27-1.99, P<0.001) and anastomotic leak (HR 2.17, 95% CI 1.24-3.78, P<0.01) were independently associated with cancer-specific survival in colon cancer. On multivariate analysis, only age ≥75 (HR 1.58, 95% CI 1.14-2.18, P<0.01) was associated with cancer-specific survival in rectal cancer. Age, presentation and anastomotic leak hazards could be simply added to form a clinical risk score from 0 to 2 in colon cancer. In patients with Dukes B stage colon cancer, the cancer-specific survival at 5 years for patients with a cumulative score 0 was 81%, 1 was 67% and 2 was 63%. The cancer-specific survival rate at 10 years for patients with a clinical risk score of 0 was 72%, 1 was 58% and 2 was 53%. CONCLUSION: The results of this study, in a mature cohort, introduce a new simple clinical risk score for patients undergoing surgery for Dukes B colon cancer. This provides a solid foundation for the examination of the impact of additional factors and treatment on prediction of 3-, 5- and 10-year cancer-specific survival.

The impact of young age on cancer-specific and non-cancer-related survival after surgery for colorectal cancer: 10-year follow-up.

BACKGROUND: It has been reported that although young patients present with more advanced disease, when adjusted for stage, cancer-specific survival is not different after surgery for colorectal cancer. However, few studies have examined non-cancer survival in young patients and 10-year survival has rarely been reported. Moreover, the largest study included patients of old age as a comparator. The aim of this study was to compare cancer-specific and non-cancer-related survival at 10 years in a young age cohort and a middle age cohort in patients undergoing surgery for colorectal cancer. METHODS: Two thousand and seventy seven patients who underwent surgery for colorectal cancer between 1991 and 1994 in 11 hospitals in Scotland were included in the study. Ten-year cancer-specific and non-cancer-related survival and the hazard ratios (HR) were calculated according to age groups (<45/45-54/55-64/65-74 years). RESULTS: On follow-up, 1066 patients died of their cancer and 369 died of non-cancer-related causes. At 10 years, overall survival was 32%, cancer-specific was 45%, and non-cancer-related survival was 72%. On multivariate analysis of all factors, sex (HR 0.77, 95% CI 0.68-0.88, P<0.001), mode of presentation (HR 1.64, 95% CI 1.44-1.87, P<0.01), Dukes' stage (HR 2.69, 95% CI 2.49-2.90, P<0.001), and specialisation (HR 1.24, 95% CI 1.04-1.44, P<0.01) were independently associated with cancer-specific survival. On multivariate analysis of all factors, age (HR 2.46, 2.04-2.97, P<0.001), sex (HR 0.56, 0.45-0.70, P<0.001), and deprivation (HR 1.16, 1.10-1.24, P<0.001) were independently associated with non-cancer-related survival. CONCLUSION: The results of this study confirm that young age does not have a negative impact on cancer-specific survival. Moreover, they show that, with 10-year follow-up, young age does not have a negative impact on non-cancer-related survival.

The impact of old age on cancer-specific and non-cancer-related survival following elective potentially curative surgery for Dukes A/B colorectal cancer.

Previous studies have suggested that survival following surgery for colorectal cancer is poorer in the elderly. However, the findings were inconsistent and none of the studies adjusted for case mix. The aim of this study was to establish whether there were age-related differences in cancer (colorectal)-specific and non-cancer (colorectal)-related survival in patients undergoing elective potentially curative resection for Dukes stage A/B colorectal cancer. One thousand and forty three patients who underwent elective potentially curative resection for Dukes' A/B colorectal cancer between 1991 and 1994 in 11 hospitals in Scotland were included in the study. Ten year cancer-specific and non-cancer-related survival and the hazard ratios were calculated according to age groups (<64; 65-74/>74 years). On follow-up 273 patients died of their cancer and 328 died of non-cancer-related causes. At 10 years, overall survival was 45%, cancer specific was 70% and non-cancer-related survival was 64%. On multivariate analysis of all factors, age (HR 1.38, 95% CI 1.18-1.62, P<0.001), sex (HR 1.74, 95% CI 1.36-2.23, P<0.001), site (HR 1.42, 95% CI 1.11-1.81, P<0.01) and Dukes' stage (HR 1.71, 1.19-2.47, P<0.01) were independently associated with cancer-specific survival. On multivariate analysis of all factors, age (HR 2.14, 1.84-2.49, P<0.001), sex (HR 1.43, 1.15-1.79, P<0.01) and deprivation (HR 1.30, 1.09-1.55, P<0.01) were independently associated with non-cancer-related survival. The results of this study show that increasing age impacts negatively both on cancer-specific and non-cancer-related survival following elective potentially curative resection for node-negative colorectal cancer. However, the effect of increasing age is greater on the non-cancer-related survival. These results suggest that cancer-specific and non-cancer-related mortality should be considered separately in survival analysis of these cancer patients.

The relationship between tumour proliferative activity, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer.

BACKGROUND: The aim of the present study was to examine the relationship between Ki-67, C-reactive protein and cancer-specific survival in patients undergoing resection for colorectal cancer. METHOD: One hundred and forty-seven patients undergoing potentially curative resection for colorectal cancer had preoperative C-reactive protein concentrations and tumour Ki-67 labelling index measured. RESULTS: On univariate analysis, age (P < 0.001), Dukes stage (P < 0.001), C-reactive protein (P < 0.001) and expression of Ki-67 (< 0.01) were associated with poorer cancer-specific survival. Ki-67 labelling index and C-reactive protein were correlated (r(s) = 0.172, P = 0.037). On multivariate analysis, age (HR 1.96, 95% CI 1.26-3.04, P = 0.003), Dukes stage (HR 4.38, 95% CI 2.11-9.09, P < 0.001) and C-reactive protein (HR 4.09, 95% CI 2.04-8.24, P < 0.001) retained significance. CONCLUSION: Increased tumour proliferation is associated with a systemic inflammatory response and poor cancer-specific survival in patients undergoing potentially curative surgery for colorectal cancer.

Postoperative serum urea is associated with 30-day mortality in patients undergoing emergency abdominal surgery.

BACKGROUND: Emergency abdominal surgery carries considerable postoperative morbidity and mortality. Hypovolaemia is considered to be a cause of renal hypoperfusion, which is associated with a decreased clearance of serum urea and creatinine. This study examines whether the perioperative serum urea and creatinine concentrations are predictors of mortality in patients undergoing emergency abdominal surgery. METHODS: Consecutive patients (n=300) who underwent emergency abdominal surgery were studied. Age- and sex-specific reference intervals were used for the data analysis. Patients with incomplete biochemical (n=51) or mortality data (n=31) or with pre-existing renal failure (n=9) were excluded from the analysis. RESULTS: 209 patients were analysed, of whom 162 (78%) remained alive and 47 (22%) died following surgery. The non-survivors were older (P<0.05), had undergone more extensive surgery (P<0.001) and were more likely to have been admitted to the intensive care unit (P<0.001). The serum urea concentration was higher preoperatively (P<0.05) and on day one postoperatively (P<0.001) in the non-survivors. On multivariate logistic regression analysis, age (odds ratio [OR] 3.27, 95% confidence interval [CI] 1.43-7.47, P<0.005), severity of surgery (OR 2.21, 95% CI 1.14-4.29, P<0.019), admission to intensive care (OR 0.54, 95% CI 0.11-0.54, P<0.001), seniority of anaesthetist (OR 0.50, 95% CI 0.27-0.90, P<0.022) and day one urea (OR 3.33, 95% CI 1.39-7.99, P<0.007) were independently associated with 30-day mortality. CONCLUSIONS: These results indicate that an increased serum urea concentration, but not serum creatinine concentration, in the postoperative period is associated with an increase in 30-day mortality in patients undergoing emergency abdominal surgery.

Low-density lipoprotein metabolism in mice with soft tissue tumours.

This study examines the potential value of low-density lipoprotein (LDL) as a vehicle for directing cytotoxic drugs to tumour cells in mouse model systems. Control and MAC 13 tumour-bearing NMRI mice were injected with tracer doses of 125I-labelled native and cyclohexanedione-modified 131I-labelled LDL. 18 h later the animals were killed and the radioactivities assimilated by various tissues were measured relative to plasma activity at the time of death. These values were used to calculate specific tissue receptor-mediated LDL uptake. All tissues expressed receptors but the liver and adrenal gland were particularly active. In tumour-inoculated animals, the neoplastic lesions were second only to liver in their net assimilation of LDL. CFLP mice bearing virus-induced parotid adenomata gave results similar to those obtained in NMRI animals. In order to improve the selectivity of LDL assimilation we attempted to downregulate LDL receptors in the liver and adrenal gland by administration of the bile acid sodium taurocholate or by subcutaneous injection of hydrocortisone sodium succinate. These manoeuvres together reduced uptake of the lipoprotein into both organs without affecting tumour activity.

Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil.

PURPOSE: A phase I and pharmacokinetic trial was performed between October 1993 and June 1994 to determine the maximum-tolerated dose of hepatic arterial infusion (HAI) of fluorouracil (5-FU) and intravenous (IV) leucovorin (folinic acid; FA) in patients with hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Forty-three patients received 310 courses of HAI chemotherapy administered over 48 hours every 2 weeks. The regimen consisted of FA 200 mg/m2 by IV infusion over 2 hours, followed by a loading dose of 5-FU 400 mg/m2 by HAI over 15 minutes, followed by a 22-hour infusion of 5-FU at doses ranging from 0.8 to 1.84 g/m2, with identical chemotherapy on day 2. Pharmacokinetic studies were performed to determine peak and steady-state plasma concentrations (Css) of 5-FU. RESULTS: Severe diarrhea and cardiac and neurologic toxicity were dose-limiting at 1.84 g/m2. The recommended dose for the 22-hour component of the schedule was 1.6 g/m2 and was associated with tolerable toxicity. A Css of 2.2 +/- 0.8 mumol/L for 5-FU was achieved on the recommended schedule, which compares favorably with conventional IV 5-FU regimens. Among 30 patients assessable for response, there were four complete responses and seven partial responses, and 12 patients with stable disease and seven with progressive disease, reported after 3 months (ie, six cycles) of therapy. CONCLUSION: A regimen that combines 5-FU and FA has been identified for regional chemotherapy in patients with hepatic metastases from colorectal cancer. The systemic levels of 5-FU achieved are similar to the conventional IV de Gramont regimen using an identical schedule of 5-FU and FA, which implies that this chemotherapy has the best of both worlds, ie, a regional advantage in delivering high drug concentrations to the target organ with adequate systemic cover for extrahepatic micrometastases.

Clinical pharmacokinetic advantages of new drug delivery methods for the treatment of liver tumours.

Response rates following systemic chemotherapy for hepatic tumours are disappointing. The drugs used have a narrow therapeutic ratio, which limit the scope for dose escalation of these potentially toxic agents. Therefore, alternative delivery methods that optimise the efficacy of currently available cytotoxic agents have been explored. Several novel approaches have attempted to 'target' treatment so that it reaches the tumour whilst minimising systemic exposure. There is some evidence to suggest that certain agents, including monoclonal antibodies and liposomes, selectively lodge in tumours following intravenous administration. Alternatively, the route of administration may be modified to enhance targeting of the administered drug. Delivery via the hepatic arterial, portal venous, and peritoneal routes as well as drug delivery via direct implantation may provide certain pharmacokinetic advantages. Infusion rates may be adjusted to optimise the pharmacokinetic profile. Chemoembolisation with microspheres, microcapsules or macromolecules might enhance targeting further. Variations in particle characteristics or by modifying hepatic arterial blood flow with vasoactive substances may be used to further refine this technique. The ultimate 'magic bullet', which allows total delivery of treatment to malignant cells whilst eliminating exposure of healthy tissues to these toxic agents, has not been developed as yet. However, currently available techniques allow considerable dose escalation that, whilst not providing a significant survival advantage, certainly improves response rates.

Glass yttrium-90 microspheres for patients with colorectal liver metastases.

Total calculated uniform liver doses of up to 150 Gy were achieved using glass yttrium-90 microspheres administered via the hepatic artery and targeted to tumour using angiotensin II in seven patients with colorectal liver metastases. No toxicity was observed. Hepatic metastatic progression was delayed in six patients. Median survival was 11 months (range 5-25 + months).

The effect of angiotensin II on tumor blood flow and the delivery of microparticulate cytotoxic drugs.

Colorectal hepatic metastases have a notoriously poor response to conventional systemic chemotherapy. We have synthesised cytotoxic drug (doxorubicin and mitomycin C) containing spheres 40 microns in diameter, using human albumin and ethyl cellulose as matrices. Introduction of these cytotoxic microspheres into the hepatic artery should embolise to the tumor and provide a controlled release depot for the anticancer agent. The vasoconstrictor, angiotensin II (AII) has been shown to increase tumor blood flow relative to normal tissue when administered via the hepatic artery, therefore we have investigated the effect of AII on targeting of cytotoxic microspheres to hepatic metastases. Patients with hepatic metastatic colorectal carcinoma had hepatic arterial catheters inserted at laparotomy and connected to subcutaneous injection ports. Peroperatively, 99mTc-labelled albumin microspheres were administered via the arterial catheter. Fifteen minutes later, AII was infused (10 micrograms per minuter for 4 min) via the catheter and 131I-labelled albumin microspheres were administered as a bolus at the midpoint of the AII infusion. Multiple biopsies were taken of normal liver and tumor metastasis and the tissue radioactivity counted for 99mTc and 131I. Further studies were performed postoperatively in which 99mTc-labelled microspheres were administered via the hepatic artery catheter and their distribution was followed using tomographic SPECT scanning. Combined results of this study suggested that AII can increase tumor SPECT scanning. Combined results of this study suggested that AII can increase tumor blood flow rates relative to normal hepatic tissue by approximately 3-fold.

Longitudinal study of resting energy expenditure, body cell mass and the inflammatory response in male patients with non-small cell lung cancer.

The aim of this study was to examine the inter-relationship between the inflammatory response and resting energy expenditure in patients with non-small cell lung cancer (NSCLC) before and after the onset of weight loss. Healthy subjects (n=7) and patients with NSCLC without weight loss (n=12) were studied. Resting energy expenditure adjusted for metabolically active tissue, as measured by total body potassium, was approximately 15% higher in the NSCLC group (P<0.01). Moreover, the resting energy expenditure, correlated with the magnitude of the inflammatory response (r=0.753, P<0.01). Six cancer patients subsequently lost weight and the relationship between resting energy expenditure and the inflammatory response was maintained. These results highlight the impact of the inflammatory response on the increase in the resting energy expenditure which precedes the onset of weight loss in patients with NSCLC.

Functional and structural changes of the human proximal small intestine after cytotoxic therapy.

The effects of cytotoxic therapy on the structure and function of the proximal jejunum were studied in six patients receiving intravenous cyclophosphamide (300 mg/m2), methotrexate (40 mg/m2), and 5-fluorouracil (600 mg/m2) as adjuvant therapy for breast cancer. Using a steady state, triple lumen tube perfusion system the absorption of water and electrolytes was measured before and 48 h after administration of the cytotoxic agents. Jejunal biopsies were obtained at each perfusion. Median (range) water absorption fell from 126 (40-142) to 84 (46-142) ml/h/30 cm, with parallel changes for electrolytes; none of the changes was significant. Brush border disaccharidases did not change at 48 h after chemotherapy, while mature enterocytes appeared normal by both light and electron microscopy. Crypt cells and immature enterocytes, however, showed focal vacuolation by light microscopy, corresponding to the occurrence of large residual bodies (secondary lysosomes) containing partially degraded fragments of damaged crypt cells. The confinement of ultrastructural changes to the immature cell population may explain the failure of this study to show a consistent change in the absorptive function of the jejunum 48 h after chemotherapy.

Prognostic value of ploidy of primary tumour and nodal secondaries in colorectal cancers.

Tumour ploidy is of prognostic value in colorectal cancer, DNA aneuploid tumours having a worse outlook. Nearly all studies have concentrated on the DNA content of the primary tumour. We have examined the ploidy of the primary tumour and its lymph node metastases in 71 cases of Dukes' stage C disease, to see whether this provides greater prognostic information than the primary alone. Analysis was performed using formalin-fixed, paraffin-embedded tumour sections. Ploidy of primary and metastases was different in 20 cases (28%), aneuploid nodes being seen with diploid primaries and vice versa. Ploidy of both the primary (chi 2 = 4.86, P = 0.03) and secondary (chi 2 = 4.86, P = 0.03) tumours predicted survival in univariate analysis. Combining the ploidy of primary and nodes, three prognostic groups could be defined--diploid primaries with diploid metastases (hazard relative to both aneuploid, 0.36) had significantly better survival than cases where the ploidy of the primary and nodes were mixed (relative hazard 0.47-0.56), which did better than cases with aneuploid primary and nodes. This study demonstrates that ploidy variation between primary and secondary tumours is common, and better prognostic information may be gained by studying both.

Survey of antibiotic prophylaxis in gastrointestinal surgery in Scotland--5 years on.

The results of a 5-year follow-up survey of the use of prophylactic antibiotics in gastrointestinal surgery in Scotland are reported. There have been significant increases in the routine use of prophylactic antibiotics during elective cholecystectomy (21% to 53% of surgeons; P less than 0.001) and appendicectomy (49% to 79% of surgeons; P less than 0.001). In addition a substantial number of surgeons used prophylactic antibiotics in selected high risk patients undergoing biliary tract surgery and gastroduodenal surgery.

The relationship between intraoperative contamination of the lower respiratory tract and postoperative chest infection.

The relationship between intraoperative contamination of the lower respiratory tract and postoperative chest infection was studied in 193 patients undergoing biliary tract surgery. During surgery, sputum was obtained from the lower respiratory tract for bacteriological culture. The diagnosis of postoperative pulmonary complications was based on clinical criteria, supported by the pattern of sequential blood gas changes in the postoperative period. Chest infection was present in 30% of patients who harboured Haemophilus species in their sputum at the time of surgery compared with 10% of those with negative cultures. Contamination of the lower respiratory tract at operation by Haemophilus sp. is associated with development of postoperative chest infection.

The value of oral antibiotic prophylaxis in biliary tract surgery.

In this study the relationship between the presence or absence of organisms in bile or on closing wound swabs and the subsequent development of wound sepsis was confirmed. There was no significant difference in the incidence of septic complications among three treatment groups in which cefuroxime (iv) and ciprofloxacin (iv or oral) were administered. Consideration of costs attributable to the choice of antibiotic prophylaxis suggests that oral ciprofloxacin in biliary tract surgery may offer significant advantages.

Oral ciprofloxacin as prophylaxis in gastroduodenal surgery.

One hundred and fifty patients undergoing gastroduodenal surgery were randomly allocated to receive intravenous (iv) cefuroxime, iv ciprofloxacin or oral ciprofloxacin as prophylaxis. There were no differences in the incidence of postoperative infection complications or duration of stay among the three groups. Oral ciprofloxacin offers obvious advantages in terms of ease of administration and cost.

Parenteral ketorolac: opiate-sparing effect and lack of cardiorespiratory depression in the perioperative patient.

Two studies evaluated the intraoperative and postoperative use of ketorolac, a nonopioid analgesic. Compared with the opioid analgesic alfentanil, ketorolac administered intraoperatively exerted no adverse effects on cardirespiratory functions (i.e., no changes in heart rate, arterial partial pressure of carbon dioxide, or mean arterial pressure, and no associated apnea). Analgesic efficacy of both agents was judged to be equal. The study of postoperative infusion of ketorolac in combination with patient-controlled administration of morphine confirmed the analgesic efficacy of ketorolac when used after upper abdominal surgery. The narcotic-sparing effect was demonstrated by the finding that patients who received placebo self-administered over 40% more morphine in the first 24 hours after surgery than those in the ketorolac group. The better pain scores with ketorolac may be associated with the reduction in unpleasant morphine-related side effects or with the provision of continuous background analgesia. The lack of respiratory depression with ketorolac, which would be anticipated from its inability to bind to central opioid receptors, was also demonstrated. In the placebo group, arterial partial pressure of carbon dioxide was significantly increased postoperatively, whereas a similar increase was not found in the ketorolac group. Results of the two investigations demonstrate the absence of opioid effects with ketorolac, and support its use for intraoperative and postoperative analgesia in patients undergoing major surgery.

Mitoxantrone and methotrexate chemotherapy with and without mitomycin C in the regional treatment of locally advanced breast cancer.

Fifty patients with locally advanced breast cancer received regional chemotherapy delivered angiographically via the internal mammary artery and varying vessels supplying the lateral aspect of the breast. Thirty three patients received mitomycin C, methotrexate and mitoxantrone, and 17 patients received methotrexate and mitoxantrone only. There was no significant difference in clinical response between the two groups. However, in patients who received mitomycin C, severe local skin toxicity occurred in nine patients resulting in delay of further therapy and considerable morbidity. Mitomycin C should not be administered regionally in patients with locally advanced breast cancer.

A comparison of regional and systemic chemotherapy for hepatic metastases.

A 48-year-old man with colorectal liver metastases underwent insertion of an hepatic arterial infusion catheter for regional chemotherapy. Postoperative hepatic arterial perfusion scintigraphy showed that only part of the liver was being perfused by this route. Chemotherapy was administered weekly via the catheter. In effect, part of the liver received regional chemotherapy, whereas the remainder of the organ was exposed to systemic chemotherapy. Ultrasonography demonstrated shrinkage of the metastases in the area of liver receiving regional therapy, whereas disease progression occurred in the region of liver receiving 'systemic' treatment. This patient demonstrates that tumour may respond to regional chemotherapy despite disease progression on systemic therapy and suggests that a controlled trial would yield valuable data.