Larsolof Hafström

A Systematic Overview of Chemotherapy Effects in Colorectal Cancer

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientix8e c literature are described separately (Acta Oncol 2001; 40: 155–65). This synthesis of the literature on adjuvant and palliative therapy with cytostatics for colorectal cancer is based on 208 scientix8e c articles, including eight meta-analyses and 162 randomised studies. These studies involve approximately 126800 patients. The conclusions reached can be summarized into the following points:A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on adjuvant and palliative therapy with cytostatics for colorectal cancer is based on 208 scientific articles, including eight meta-analyses and 162 randomised studies. These studies involve approximately 126,800 patients. The conclusions reached can be summarized into the following points: The benefit of postoperative adjuvant chemotherapy with fluorouracil and levamisole in patients with colon cancer stage Dukes C was demonstrated more than ten years ago in two phase III trials. There was a reduction of recurrence from 56% to 39% and reduction of death from 51% to 40% after more than five years of follow-up. Although this combination has been widely accepted as standard adjuvant treatments for stage Dukes C colon cancer, there is still debate on whether adjuvant treatment with fluorouracil alone would be equally efficacious. Several phase III trials with postoperative adjuvant chemotherapy with fluorouracil and leucovorin in patients with colon cancer stage Dukes C have demonstrated a similar statistically significant improvement in disease-free and overall survival in comparison with a control arm. Six months of treatment with fluorouracil and leucovorin is as efficient as twelve months of fluorouracil and levamisole. This treatment is, thus, recommended for routine use. No convincing benefit from adjuvant chemotherapy is proven in colon cancer stage Dukes B although some randomised trials have shown the same relative survival gain as seen in stage Dukes C. There is less knowledge on survival benefits from adjuvant chemotherapy for Dukes stage B and C rectal cancer. In small randomised trials, postoperative radiochemotherapy has, however, improved survival to the same extent as chemotherapy in colon cancer Dukes stage C. A meta-analysis of nine randomised trials revealed a small but statistically significant benefit in five-year survival and a reduction in the risk of death for the patients receiving immediate postoperative portal vein infusion compared with controls. At present, however, the use of portal vein infusion or intraperitoneal therapy outside of a research trial cannot be recommended in the light of the limited effects. This conclusion is further supported by similarly limited effects in two recently reported very large European multicentre trials. In advanced colorectal cancer, chemotherapy may prolong survival, decrease tumour-related symptoms, improve general well-being or maintain it at a high level for a longer time period compared with best supportive care. These effects have been seen using systemic chemotherapy and using regional chemotherapy in patients with metastases limited to the liver. Subjective responses and quality of life improvements are seen more frequently than objective tumour remissions. Although the impact on overall survival is modest, i.e. an improvement in median survival of five to six months, treatment is recommended also outside clinical trials. High-dose infusional regimens with modulated fluorouracil may turn out to be superior to conventional bolus regimens, since they result in more tumour regressions, longer times to disease progression and possibly longer survival. A plateau seems, however, to have been reached with fluorouracil, giving objective response rates of up to 30% to 40% with a variety of modulators. Randomised studies of regional therapy, mostly hepatic arterial infusions, of liver metastases in colorectal patients have demonstrated significantly higher response rates than systemic fluorouracil therapy alone without impact on overall survival. The importance of the higher response rates for patient benefit in the predominantly asymptomatic patients with isolated liver metastasis remains to be elucidated. Regional therapy in advanced disease cannot be recommended outside of clinical trials. New cytotoxic agents are emerging with antitumour activity similar to fluorouracil-based chemotherapy. The addition of oxaliplatin or irinotecan to existing fluorouracil regimens improves response rates and duration of response, and possibly overall survival. Based upon the results of two randomised studies, there is a role for irinotecan as second line therapy for selected patients who have failed first-line therapy with fluorouracil plus leucovorin. The role of these agents, alone or in combinations, in clinical routine remains, however, to be determined due to more pronounced toxicity than caused b

A Systematic Overview of Chemotherapy Effects in Pancreatic Cancer

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40:155-65). The conclusions of this overview in pancreatic cancer are based on 10 randomised studies with, and 18 randomised studies without, an untreated control group. Altogether, 4,028 patients were included in the phase III studies. Furthermore, 32 phase II studies or retrospective analyses including 1,404 patients have been evaluated. The conclusions reached can be summarized into the following points: There is no convincing evidence that pancreatic cancer patients benefit from adjuvant chemotherapy treatment, with or without concomitant radiotherapy. Adjuvant chemotherapy in patients with pancreatic cancer should thus not be used routinely. In locally advanced/metastatic pancreatic cancer, six randomised trials comparing combination chemotherapy with an untreated control group were retrieved. In three trials, two of which were performed recently, chemotherapy provided statistically significant prolongation in median survival in the range of three to nine months. The three other trials, all reported in the early 80s, essentially showed no difference in survival between the treatment groups. In the locally advanced/metastatic setting there are also several randomised trials comparing various chemotherapy regimens. Except for an improvement in median survival of one to two months from gemcitabine compared with 5-FU, no differences were observed. There is no convincing evidence that a large fraction of pancreatic cancer patients will benefit from palliative chemotherapy. The few open-design studies that have explored the influence on symptom relief/quality of life indicate that between 20-35% of the patients get clinical benefit, but usually short-lived. Recently performed randomised studies, all using adequate methodology, indicate that the beneficial effects observed in advanced pancreatic cancer are similar to those of accepted therapy in other cancer types. However, due to the limited positive effects, palliative chemotherapy in pancreatic cancer can only be recommended selectively and should preferably be used within controlled clinical trials exploring new treatment combinations or concepts.A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientix8e c literature are described separately (Acta Oncol 2001; 40: 155–65). The conclusions of this overview in pancreatic cancer are based on 10 randomised studies with, and 18 randomised studies without, an untreated control group. Altogether, 4028 patients were included in the phase III studies. Furthermore, 32 phase II studies or retrospective analyses including 1404 patients have been evaluated. The conclusions reached can be summarized into the following points:

p53 Mutations in primary tumors and subsequent liver metastases are related to survival in patients with colorectal carcinoma who undergo liver resection

The appearance of p53 mutations in colorectal carcinoma was determined, independent of differentiation and tumor stage of the primary tumors, in relation to the survival of patients who were scheduled to undergo liver resection.

Type IV collagen as a tumour marker for colorectal liver metastases

BACKGROUNDnAbout 50% of patients with primary colorectal cancer (CRC) will develop liver metastases (CLM). Currently, carcinoembryonic antigen (CEA) is the most common tumour marker for CRC and CLM. However, the sensitivity and specificity of this marker is not optimal, as almost 50% of patients have tumours that do not produce CEA. Therefore there is a need for better markers for CRC and CLM.nnnMETHODSnThe circulating levels of type IV collagen were measured in patients with CLM, primary CRC and in healthy controls. The expression pattern of type IV collagen was studied by immunofluorescence in CLM and normal liver tissue. The metastatic volume of CLM in the liver was estimated from CT.nnnRESULTSnIn CLM tissue type IV collagen is highly expressed in the areas of desmoplasia. Patients with primary CRC (Dukes A-C) did not show any increase in circulating type IV collagen compared to healthy controls. However, patients with CLM have significantly elevated levels of circulating type IV collagen when compared to patients with primary CRC and healthy controls. The levels of type IV collagen decreased during chemotherapy and increased at the time of disease progression. The circulating levels of type IV collagen seem to reflect the tumour burden in the liver.nnnCONCLUSIONSnType IV collagen has the potential to be used as tumour associated biomarker for CLM. These results indicate the importance of interaction between cancer cells and the stroma in the tumour microenvironment.

Phagocytosis and dynamic RES scintigraphy: an evaluation of commercial colloids in rats.

Reticuloendothelial system (RES) phagocytic function or capacity can be measured by clearance studies with test substances. This study in the rat examines three commercially available 99BTcm-labelled test substances, and different methods of calculating RES capacity. Albures size 500 nm and sulphur colloid size 600 nm used for liver scintigraphic imaging and Nanocoll size 50 nm used for bone-marrow scintigraphic imaging were tested. The rats were examined under a gamma camera and the uptake by the liver, clearance from the heart and clearance from blood samples were recorded. Different amounts of substances were tested. The final uptake in different organs was recorded after the animals were sacrificed. Colloid size and stability were tested with a polycarbonate filter. (Nanocoll was found to have at least 10 times smaller colloid diameter, leading to a thousand times more particles per milligram). RES function was calculated as the uptake rate or clearance rate, k. In a logarithmic plot, the relationship between uptake or clearance and time was found to be linear between 90 and 300 s and calculations of k in this interval are recommended, k-values selected from blood sample curves were 11±5 S.E.M. lower than those calculated from heart clearance curves or liver uptake curves. Increasing amounts of Nanocoll caused a decrease in uptake rate k. Albures and sulphur colloid could not be given in amounts that caused any change in k. Only Nanocoll could be given in sufficiently large amounts (above the critical dose) to challenge RES and avoid complete extraction from the circulation during first passage through RE organs. Nanocoll seems suitable for use in tests of RES function and the optimal amount was 0.03 mg per rat (0.6 x 1012 particles).

A comparison between hepatic artery ligation and portal 5-Fu infusion versus 5-Fu intra arterial infusion for colorectal liver metastases.

AIMnA prospective randomized study was executed comparing two regimens of regional therapy for liver metastases from colorectal cancer.nnnMETHODSnEighteen patients were allocated to hepatic artery occlusion for 16 h followed by intraportal 5-fluorouracil (5-Fu) infusion (1000 mg/m(2)) for 5 days every sixth week (HAO). Twenty-one patients received intra-arterial 5-Fu infusion+Leucovorin (100 mg) i.v. for 2 days every second week (HAI). The follow up every third month included CT and CEA. Thirteen patients had limited extrahepatic cancer. At tumor progression regional therapy was stopped and systemic chemotherapy or the best supportive care was administered.nnnRESULTSnThe study was discontinued after randomization of 39 patients. No significant difference in survival within patients with and without extrahepatic cancer was present. The mean survival was longer in the HAI group than for the HAO group (19 months versus 13 months, p=0.0147) (median 18 (8-37) versus 12 (2-26). PR and SD were registered in 8/18 in the HAO group and 17/21 patients in HAI group. The median time to progress was 4 (1-22) months versus 7 (1-23) months for the HAO and HAI group, respectively.nnnCONCLUSIONnRegional intraarterial infusion with 5-Fu gives significantly better survival than hepatic artery occlusion followed by portal infusion. A limited amount of extrahepatic cancer does not influence survival time. A trial comparing hepatic artery 5-FU infusion and Leucovorin versus the most effective systemic therapy is warranted.

Digitonin enhances the efficacy of carboplatin in liver tumour after intra-arterial administration

Abstractu2003Platinum-containing drugs enter the cell slowly and have a poor tissue penetration. Increasing the permeability of the cell membrane might increase the intracellular drug concentration. Digitonin, a detergent that increases cell permeability by binding to cholesterol molecules in the cell membrane, can increase cisplatin accumulation and reduce tumour growth in vitro. The aim of this study was to determine whether digitonin could increase the efficacy of carboplatin (CBDCA) in vivo. In LH rats, a hepatoma was implanted in the liver. At 7 days after implantation, digitonin (or saline in the control group) was infused via the hepatic artery and, 10 min later, CBDCA was injected. Biopsies from the tumour and liver parenchyma were obtained after 1 h. The concentration of platinum measured in the liver tumours was higher in the digitonin group than in the control groups. In the liver parenchyma the concentrations were of the same magnitude. Measured with the 133Xe-clearance technique, digitonin did not alter the tumour blood flow. Digitonin enhanced the tumour-growth-retarding effect of CBDCA given intra-aterially at 5 mg/kg but not at 25 mg/kg. No increase in toxicity was observed for digitonin given together with CBDCA at 5 mg/kg. Systemic administration of CBDCA was not influenced by digitonin. These findings demonstrate that pretreatment with digitonin increases the tumour uptake of CBDCA and potentiates the cytotoxic effect of CBDCA.

Influence of zymosan (a non-specific macrophage stimulator) and of indomethacin on liver tumours : an experimental study in rats

Zymosan—a non-specific macrophage-stimulating agent-reduces tumour take in the liver. The mechanism for this effect is not clear, but it may be mediated via the Kupffer cells and prostaglandins. On the other hand, the Prostaglandin-synthesis inhibitor, indomethacin, inhibits tumour growth. Pretreatment with zymosan (3 mg 100 g−1) for 3 days of two different strains of rats, inoculated in the liver with a hepatoma or an adenocarcinoma cell suspension respectively, reduced tumour take and also initial tumour growth. The effect on tumour take and initial growth was inhibited by concomitant administration of indomethacin (0.2 mg 100 g−1). When zymosan was administered after tumour cell inoculation the growth rate of the hepatoma was retarded, but this effect was not abrogated by indomethacin. Pretreatment with indomethacin had no significant effect on tumour take or initial growth. When given after the tumour was established in the liver, indomethacin reduced the growth rate of the hepatoma, but not of the adenocarcinoma. These results suggest that there are different mechanisms for the effects of zymosan on tumour take and on growth of an established tumour. In immunoincompetent nude mice the effect on the hepatoma was similar to the effect in the rat. In vitro both tumours were insensitive to zymosan and indomethacin. This study confirms that pretreatment with a non-specific macrophage stimulator (zymosan) diminishes tumour take and growth in the liver, that the effect of zymosan on tumour take in the liver is abrogated by indomethacin and that the zymosan effect on tumour take in the liver is at least partly mediated by the Kupffer cells and prostaglandins.

Antitumour effects of pure diastereoisomers of 5-formyltetrahydrofolate in hepatic transplants of a rodent colon carcinoma model

The effects of the two diastereoisomers of 5-formyltetrahydrofolate on tumour growth, thymidylate synthase (TS, EC 2.1.1.45) levels, and potentiation of 5-fluorouracil cytotoxicity were studied in an in vivo rat colon carcinoma model, transplanted to liver. The animals were randomized into eight groups, treated with daily i.v. tail vein injections of racemic (d,l)-5-formyltetrahydrofolate (5-CHO-FH4), 15 mg/kg, (1)-5-CHO-FH4 7.5 mg/kg, and (d)-5-CHO-FH4 7.5 mg/kg, 5-fluorouracil (FUra) 30 mg/kg, (d,l)-5-CHO-FH4 15 mg/kg+FUra 30 mg/kg, (l) 5-CHO-FH4 7.5 mg/kg+FUra 30 mg/kg, and (d)-5-CHO-FH4 7.5 mg/kg+FUra 30 mg/kg, and a sham-treated control group. The average tumour size of the groups was equal at the start of treatment. After six days treatment the average tumour sizes were at laparotomy 3.3 +/- 1.0 g in the (d/l)-5-CHO-FH4 treated group, compared to 2.0 +/- 0.1 g in the FUra treated group and 7.1 +/- 3.1 g in the controls. Natural (l)-5-CHO-FH4 promoted tumour growth (average tumour weight 10.8 +/- 4.0 g), whereas the unnatural (d)-5-CHO-FH4 alone retarded it (average tumour weight 1.2 +/- 0.40 g). (l)-5-CHO-FH4 induced a significant increase in tumour tissue TS levels by [3H]FdUMP radioligand assay (27.5 +/- 8.4 pmol/g tumour tissue) compared to controls (16.8 +/- 6.1 pmol/g tumour tissue). Increases in 5,10-methylenetetrahydrofolate and tetrahydrofolate occurred with FUra alone, with a further statistically significant increase in both folates with the addition of (d)-5-CHO-FH4 to FUra.

Leukocyte Activation by Isolated Hyperthermic Liver and Limb Perfusion due to Malignancy

Fourteen patients with liver tumor malignancy and sixteen patients with malignant melanoma localized to one limb were studied regarding leukocyte activation with the release of polymorphonuclear neutrophilic (PMN) elastase and of neopterin and formation of cytokines (TNF-α and Il-6) during the surgical treatment. Patients undergoing liver resection (n=10), abdominal hysterectomy (n=10), or hip replacement surgery (n=10) served as control groups. Isolated hyperthermic liver perfusion was performed with cytostatic-containing perfusate (melphalan and cisplatinum). Patients with recurrent malignant melanoma confined to one limb underwent isolated hyperthermic limb perfusion with cytostatic-containing perfusate (melphalan). Blood samples for determination of PMN elastase, neopterin, TNF-α, and IL-6 were drawn from the patients preoperatively, 1 minute before the start of the perfusion, 60 and 120 minutes after the start of the perfusion, and 24 hours postoperatively. Samples from the perfusate were drawn 60 minutes after the start of the perfusion. High concentrations of plasma PMN clastase were found both in patients undergoing liver and limb perfusion and in patients undergoing liver resection surgery. Elevated concentrations of Il-6 were found in the patients undergoing liver perfusion and in patients undergoing liver resection. In none of the patients were there increased concentrations of neopterin or TNF-α. The perfusate contained high concentrations of PMN elastase, neopterin, and IL-6. This study also demonstrated that major surgery leads to elevated concentrations of PMN elastase and IL-6. An increase of PMN elastase and IL-6 was seen in response to perfusion and to surgical trauma.RésuméQuatorze patients ayant une tumeur maligne du foie et 16 patients ayant un mélanome malin localisé à une extrémité ont été étudiés en ce qui concerne lactivation des leucocytes associée à un relargage délastase PMN et de néoptérine ainsi que la formation de cytokinines (TNF-α et IL-6) pendant le traitement chirurgical. Trente patients avant eu soit une résection hépatique (n=10), soit une hystérectomie abdominale (n=10) ou une prothèse de hanche (n=10) ont servi de témoins. On a perfusé le foie avec un perfusât de cytostatiques (mélphalane et cis-platine). Les patients ayant un mélanome malin dune extrémité ont eu une perfusion isolée hyperthermique avec une perfusion de cytostatique (mélphanane). Des échantillons du sang ont été retirés pour déterminer les taux délastase PMN, de la néoptérine, du TNF-α, et de lIL-6 en préopératoire, une minute avant le début de la perfusion, 60 et 120 minutes après le début de la perfusion, et 24 heures postopératoirement. Des échantillons ont été retirés 60 minutes après le début de la perfusion. Des concentration élevées délastase PMN ont été retrouvées à la fois chez les patients ayant une perfusion hépatique et de lextrémité et chez les patients ayant eu une résection du foie. Des concentration élevées en IL-6 ont été retrouvées chez le patient ayant une perfusion du foie et chez le patient ayant une résection hépatique. Les concentrations en néoptérine et en TNF-α nétaient pas élevées. Le liquide de perfusion contenait des concentrations élevées en élastase PMN, néoptérine et en IL-6. Cette étude démontre aussi que la chirurgie majeure est associée avec des concentrations élevées en PMN elastase et IL-6. Une augmentation en PMN-élastase et en IL-6 a été retrouvée en réponse à la perfusion et au traumatisme chirurgical.ResumenCatorce pacientes con tumores malignos del hígado y 16 pacientes con melanoma maligno localizado en una extremidad fueron estudiados en relación con la activación de leucocitos con liberación de elastasa de PMN y de neopterina y la formación de citocinas (FNT-α e IL-6) en el curso del tratamiento quirúrgico. Pacientes sometidos a resección del hígado (n=10), histerectomía abdominal (n=10) y reemplazo de cadera (n=10) sirvieron como grupos control. Se realizó perfusión hipertérmica aislada del hígado con perfusato citostácico (melfalán y cisplatino). Los pacientes con melanoma maligno recurrente confinado a una extremidad fueron sometidos a perfusión hipertérmica aislada de la extremidad con perfusato citostácico (melfalán). Se tomaron muestras de sangre para determinación preoperatoria de elastasa de PMN, neopterina, FNT-α e IL-6, un minuto antes de comenzar la perfusión, 60 y 120 minutos después del comienzo de la perfusión y 24 horas después de la operación. Se tomaron muestras del perfusato a los 60 minutos luego del comienzo de la perfusión. Se encontraron altas concentraciones de elastasa de PMN tanto en los pacientes sometidos a perfusión hepática o de la extremidad, como en los pacientes sometidos a resección hepática. Se encontraron concentraciones elevadas de IL-6 en los pacientes sometidos a perfusión hepática y en los pacientes sometidos a resección del hígado. En ningún paciente se encontraron concentraciones aumentadas de neopterina o de FNT-α. El perfusato contenía altas concentraciones de elastasa de PMN, neopterina e IL-6. Se encontró un aumento en la elastasa de PMN y en la IL-6 en respuesta a la perfusión y al trauma quirúrgico.