Adjuvant therapy in bowel cancer: its time has arrived.
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Antineoplastic Agents↗
Biomedical subjects
B N Gray
Publications and source records attributed to B N Gray.
Effect of temperature on liver tumour blood flow.
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Animals↗
Tolerance of the liver to the effects of Yttrium-90 radiation.
There are no reliable data documenting the tolerance of the human liver to ionizing radiation from a continuous Yttrium-90 source. As Yttrium-90 incorporated into microspheres is being used to treat patients with liver cancer, it is imperative that the tolerance of the human liver to this form of radiation damage be determined. Four patients with metastatic liver cancer were treated with Yttrium-90 to deliver radiation doses above that considered tolerable when given by conventional external sources. Patients were monitored with serial estimations of liver function tests and between 7 and 9 months after treatment liver biopsies were performed. Histological examination of the liver biopsies confirmed only minimal changes in the normal liver parenchyma. These data indicate that the human liver may tolerate relatively large radiation doses when delivered by Yttrium-90 microspheres embedded in the liver parenchyma as a number of discrete point sources.
Adenocarcinoma↗
Comparison of portal vein chemotherapy with hepatic artery chemotherapy in the treatment of liver micrometastases.
This study was conducted in a rat model of hepatic micrometastases generated by the intraportal injection of a colonic carcinoma cell line bound to polystyrene microspheres. Thirty-two animals received continuous infusions of 5-fluorouracil (5-FU) into either the portal vein or hepatic artery for a period of 7 days. Drug infusions were begun at 0, 2, 4, and 6 days after the time of tumor inoculation in four groups of animals, respectively. Subsequent tumor growth in these animals at 1 month was compared with tumor growth in 11 control animals that did not receive chemotherapy. When 5-FU was administered via the portal vein on the same day as tumor inoculation, liver metastases were reduced by approximately 91% (p = 0.004). Portal vein chemotherapy administered 6 days after tumor inoculation, when macroscopic nodules had a mean diameter of 0.33 +/- 0.03 mm (SE), produced no tumor response (p = 0.36). Histologic examination of these lesions revealed early invasion outside distended portal venules. In contrast, hepatic artery 5-FU infusions administered at 0, 2, 4, and 6 days after tumor implantation all reduced the subsequent development of hepatic metastases by approximately two thirds of that observed in the untreated group (p = 0.004). We conclude that hepatic artery chemotherapy may have an important complementary role to play as an adjuvant treatment for gastrointestinal cancer.
Animals↗
Low-dose systemic doxorubicin in combination with regional hepatic hyperthermia.
The influence of regional liver hyperthermia in conjunction with systemic doxorubicin administration was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450MHz microwave generator to the exteriorised livers of the rabbits to provide a thermal dose equivalent of 43 degrees C for 30 minutes. Animals receiving doxorubicin infusion were treated with a total of 1.2 mg/kg over a 3 day protocol through an ear vein. Rabbits were divided into 4 groups; a no treatment control, hyperthermia alone, doxorubicin alone and hyperthermia immediately preceded by doxorubicin. The tumour mass, 10 days post treatment was significantly (P less than 0.0001) reduced in all treatment groups. However, the mean tumour mass in the combination treatment group was also significantly lower than both treatments alone (P less than 0.001). This increased response was not accompanied by any signs of increased systemic or local toxicity associated with any treatment.
Animals↗
Selective internal radiation therapy: validation of intraoperative dosimetry.
In selective internal radiation (SIR) therapy of hepatic metastases, tumor vasculature is preferentially embolized with high-energy beta-emitting yttrium-90-labeled microspheres. To enable accurate estimation of the resultant absorbed radiation doses to tissues, an intraoperative beta detection probe is used to scan the liver surface. The validity of the response of this probe to Y-90 and its clinical application were assessed with a phantom containing varying activities and with biopsy samples obtained from patients being treated with SIR therapy. A linear relationship was found between the probe counts taken from the biopsy samples and the calculated tissue radiation doses from the specific activities of each sample. This relationship was repeated with probe counts determined against a water phantom containing various activities of Y-90. The probe was shown to respond minimally to bremsstrahlung. The use of the probe in measuring tissue radiation doses at laparotomy provides the opportunity to control dose administration during SIR therapy. In this way, subtherapeutic exposure of normal tissue can be assured while tumor tissue receives maximal radiation levels.
Brachytherapy↗
Vascularization of small liver metastases.
The portal vein contributes little to the blood supply of established liver metastases in the presence of a patent hepatic artery. However, its role in the perfusion of early metastatic liver disease remains controversial. We have quantified the relative contribution of the portal vein and hepatic artery to the internal circulation of small liver tumours. These studies were conducted in a new rat model of liver metastases generated by the intraportal injection of cultured tumour spheroids. A total of 633 lesions were studied in 18 animals using radioisotope tracer microspheres. Nodules ranged from 0.5 to 6.0 mm in diameter, 92 per cent being 3.0 mm or less. The ratio of radioactivity in tumour compared with normal tissue (T:N ratio) was determined after simultaneously injecting microspheres into the portal and arterial circulation of each animal. The mean hepatic artery T:N ratio was significantly greater than that of the portal vein for all tumour sizes studied (P less than 0.01). Nodules 0.5 mm in diameter had a mean (s.e.m.) hepatic artery T:N ratio of 1.50 (0.12) in comparison with a mean portal vein ratio of 0.13 (0.04). Tumour nodules 2.0 mm in diameter had a mean (s.e.m.) hepatic artery T:N ratio of 1.26 (0.11) in comparison with a mean portal vein ratio of 0.06 (0.01). The overall T:N ratio for both routes decreased with increasing tumour size. These results indicate that hepatic tumours as small as 0.5 mm already have an established internal vasculature perfused predominantly by the hepatic artery. In contrast, the portal vein contributes insignificantly to the internal perfusion of these lesions. These results have significant implications for adjuvant locoregional therapy in gastrointestinal cancer.
Animals↗
Controlled clinical trial of adjuvant immunotherapy with BCG and neuraminidase-treated autologous tumour cells in large bowel cancer.
A controlled, randomised clinical trial of immunotherapy was performed in 301 patients with stage B or C colorectal cancer. The immunotherapy treatment consisted of 18 vaccinations over a 2 year period following surgery with a combination of BCG given by scarification plus subcutaneous injection of Vibrio cholera neuraminidase (VCN)-modified autologous tumour cells. Five year follow-up has now been completed in all patients. The immunotherapy did not alter either the disease-free interval or the overall survival of patients in comparison with a control group of patients not receiving immunotherapy.
Adenocarcinoma↗
Selective internal radiation (SIR) therapy for treatment of liver metastases: measurement of response rate.
Ten patients with liver metastases from primary tumors in the colorectum were treated with selective internal radiation (SIR) therapy. This involved the embolisation of yttrium-90-containing microspheres into the hepatic artery at the time of laparotomy. The microspheres were concentrated in the microvasculature of the tumour nodules by the concurrent administration of angiotensin II. The radiation dose being delivered to liver parenchyma was measured at the time of operation by use of an intraoperative radiation detection probe. All nine patients in whom the preoperative carcinoembryonic antigen (CEA) level was elevated experienced a decrease in CEA levels posttreatment. Intraoperative dosimetry confirmed the poor correlation between total radioactivity used and radiation dose received by normal liver parenchyma.
Adenocarcinoma↗
Selective internal radiation therapy: distribution of radiation in the liver.
Selective internal radiation therapy for primary and secondary liver cancer involves the intra-hepatic arterial injection of microspheres containing yttrium-90. The microspheres become entrapped primarily in, and thus preferentially irradiate, tumour tissue. During a clinical trial with this therapy it has been possible to take tumour and normal liver tissue samples, after microsphere injection, and measure their specific activity. Absorbed tissue radiation doses were then calculated for tumour and normal tissue samples from a total of nine patients. The mean tumour to normal tissue ratio for radiation dose for the nine patients was approximately 6:1 with a range of 0.4:1-45:1. Injection of similar amounts of activity in different patients resulted in markedly differing tissue doses depending on liver size and tumour burden. Normal liver tissue doses of between 9 and 75 Gy were measured while corresponding tumour tissue doses ranged from 34 to 147 Gy. Selective internal radiation therapy, combined with the blood flow changes resulting from angiotensin II administration, can provide preferentially high radiation doses to tumour tissue within the liver whilst relatively sparing the surrounding normal liver tissue.
Adenocarcinoma↗
Intraoperative dosimetry of 90Y in liver tissue.
The use of an intraoperative radiation detection probe was assessed following the injection of 90Y labelled radioactive microspheres into the normal liver of 10 sheep. The absorbed dose to the liver ranged from 10 to 50 Gy. There was a linear relationship between the probe recordings and the radiation dose as measured by scintillation counting of liver tissue. By using the probe during the procedures for internal radiation therapy the injected dose of radioactive microspheres can be manipulated to provide the maximum tolerable dose to normal tissue.
Animals↗
Enhanced in vivo activity of adriamycin incorporated into controlled release microspheres.
A comparison of the cytotoxic effectiveness of adriamycin incorporated into ion exchange microspheres with conventional chemotherapeutic use of adriamycin was carried out in a rat tumour model. Drug microspheres were targeted to the tumours by embolisation into the arterial supply of the hind limb bearing the tumour. Microspheres were found to embolise in tumour tissue at concentrations of up to 39 times that of the surrounding normal tissue. As a result, adriamycin microsphere therapy was found to retard significantly (P less than 0.01) tumour growth rates compared to growth rates associated with similar doses of adriamycin delivered as free drug rather than bound to controlled release microspheres. Equivalent sham microsphere treatments showed no significant difference in tumour growth rates compared with the control group. Adriamycin loaded on to ion exchange microspheres holds strong potential for treatment of human malignancy.
Adenocarcinoma↗
Albumin microspheres as vehicles for the sustained and controlled release of doxorubicin.
Biodegradable albumin microspheres have been prepared with the intention of targeting doxorubicin preferentially to tumour tissue. A high-yielding microsphere manufacturing process has been developed that involved the denaturation of an aqueous protein emulsion by chemical and/or thermal crosslinking methods. Microspheres can be closely sized to a diameter of 25.3 +/- 2.6 microns with the aid of micro-sieves. The in-vitro release of doxorubicin from albumin microspheres was measured using a continuous flow system. Doxorubicin release can be sustained for up to 10 days and the rate of release could be controlled by manipulating protein denaturation conditions between the temperatures 110-135 degrees C in the presence of 0-2% glutaraldehyde. Release of doxorubicin was significantly faster in human plasma compared with isotonic saline.
Albumins↗
A new reproducible model of hepatic and peritoneal metastases from colonic carcinoma.
A new technique for the generation of tumour nodules in both liver and peritoneal cavity has been developed in Wistar wag rats. The cell line 192 NRc was derived from a 1,2-dimethylhydrazine (DMH)-induced colonic carcinoma and was cultured on positively charged ion-exchange polystyrene microspheres. The tumour grew to confluence on the spheres, adhering firmly by pseudopodial extensions, enabling washing and injections of spheroids without significant dislodgement of cells. 5 x 10(4) tumour spheroids injected into the portal vein produced a mean of 35 +/- 24 (S.D.) nodules in the liver with an average diameter of 1.5 +/- 0.55 (S.D.) mm at 14 days. The spheroids did not enter the hepatic veins and therefore did not produce pulmonary metastases. Similarly, 5 x 10(3) tumour spheroids injected into the peritoneal cavity, after gently abrading the peritoneum with gauze, produced a mean of 65 +/- 37 (S.D.) nodules with an average diameter of 1.6 +/- 0.39 (S.D.) mm at 14 days. The tumour continued to grow as discrete nodules in both locations until near the time of death at approx. 36 days from inoculation. This animal model is reproducible and will allow the study of a number of treatment modalities for discrete neoplastic lesions in both the liver and peritoneal cavity at any stage of tumour growth without interference from tumour at unwanted sites.
Animals↗
Effect of angiotensin II on blood flow in the transplanted sheep squamous cell carcinoma.
The effects of systemic infusion of angiotensin II on the distribution of blood flow in the sheep squamous cell carcinoma after transplantation to the liver were measured using tracer microspheres. The ratio of arterially introduced radioactive microspheres embolizing in tumour tissue compared to normal hepatic parenchyma was measured before and after infusion of angiotensin II. Doses of angiotensin II inducing increases in mean arterial blood pressure of 26 mmHg produced significant increases in the embolization ratio from 2.8 to 4.1:1. In addition, the ratio of microspheres gaining access to the necrotic centres of the tumours compared to the normal liver tissue significantly increased from 1.6 to 2.3:1. In terms of the technique of internal radiation therapy for hepatic metastases, the concurrent infusion of angiotensin II with injection of radioactive microspheres would result in a substantially enhanced radiation dose to liver tumours. At the same time the dose to normal tissue can be minimized.
Angiotensin II↗
Melbourne trial of adjuvant immunotherapy in operable large bowel cancer.
A controlled randomized clinical trial was undertaken to assess the ability of combined non-specific and specific immunotherapy to alter the disease-free interval and overall survival of patients with Stage B or C large bowel cancer. The immunotherapy consisted of a 2 year programme of vaccinations with BCG and neuraminidase-treated autologous tumour cells. Three hundred and one patients entered the trial. At 5 years of follow-up there is no evidence that this form of immunotherapy can alter either the disease-free interval or survival in this group of patients.
Antigens, Neoplasm↗
The conservative management of primary breast cancer.
A comparison was made of the methods used to manage primary breast cancer in Western Australia during 1978 and 1984. It was noted that the incidence of breast-conserving surgery increased from 5% in 1978 (16 out of 313 patients) to 14% in 1984 (59 out of 431 patients). Of the 59 patients in the latter group, 37 (63%) did not receive adjuvant radiotherapy. This is a matter of concern as failure to use adjuvant radiotherapy, subsequent to breast-conserving surgery, may lead to an increased incidence of locally recurrent disease.
Aged↗