The poor results of systemic chemotherapy for colorectal liver metastases have focussed attention on the use of regional chemotherapy. Emobolizing, biodegradable particles can be coadministered with anticancer drugs to slow temporarily the arterial blood flow and increase drug uptake within the tumour-bearing liver. Alternatively, such microspheres can be loaded with cytotoxic agents and act as slow-release mechanisms following embolization. In both instances, size and rate of degradation are important. The aim of this study was to evaluate the biological degradation of albumin microspheres in the liver of patients with colorectal liver metastases. Seven patients with advanced liver metastases had a 200–250 mg bolus dose of customized albumin microspheres (diameter range: 20–40 μm), labelled throughout with covalently bound 131I, injected into the hepatic artery. The abdomen was imaged immediately before injection to give an estimation of background count rate, and daily after injection for five days. Activity-time curves were constructed for the liver region. The median biological half-time of the particles within the whole liver was 2.4 days (range: 1.5–11.7 days), but was longer in tumours than in normal liver in some patients. The rate of microsphere degradation within tumours may be an important factor in the efficacy of microsphere-based regional therapy, and can be studied accurately by the technique we have employed.
e18259 Background: NCI instituted a Central IRB (CIRB) with voluntary participation in 2001 for its late-phase trials and demonstrated that efficiency could be improved and costs reduced (Wagner et al JCO, 2010; 28). As a forerunner to the new NIH policy for single IRBs for all NIH multi-site trials (Hudson et al. JAMA Oct 4, 2010), NCI implemented a new CIRB model in 2014 where the CIRB was the IRB of record. We report adoption data of the new model within NCI’s National Clinical Trials Network (NCTN) and lessons learned from the rollout. Methods: We reviewed: Annual CIRB participant data from 2013-2016; site/accrual data for late phase trials activated between 2013-2016 (N = 64) via CIRB or local IRBs; and data from CIRB reports to identify acceptance and lessons learned. We compared time required for CIRB protocol reviews via the new model to baseline measures in the literature. Results: Of the 2,300 U.S. NCTN sites, the percentage of participation went from 47% in 2013, to 74% (2014), 79% (2015), and 81% (2016). For activated trials, a median of 43% of sites used their local IRB in 2013, dropping to 18% in 2014, 5% in 2015, and only 1% in 2016; i.e., 99% of sites opening trials in 2016 did so using the CIRB. Annual accrual to NCTN trials remained steady through the CIRB adoption; CIRB sites represented a median of 56% of total accrual in 2013 increasing to 87% in 2016. Help-desk and survey data indicate increased acceptance and a reduction of concerns over the 3 years. Previous analyses prior to 2013 reported a median of 70-123 days required from protocol application receipt to final CIRB approval; the new model reports a median of 41 days in 2016. Conclusions: NCI has demonstrated that a single IRB for multi-site trials is not only viable but valuable. Its new CIRB model rollout over 3 years has resulted in a doubling of site adoption, high utilization rates, further efficiencies, and overall acceptance, with no noticeable effect on overall NCTN accrual. Our experiences provide important lessons learned and insights into the successful implementation of a single IRB at a national level, and support the feasibility of NIH’s recently finalized policy requiring all sites to use a single IRB for multi-site research.
Abstract The results of systemic chemotherapy in patients with liver metastases from colorectal cancer remain dismal. Regional chemotherapy has been advocated as a method of improving the delivery of cytotoxic drugs to tumour, while minimizing systemic toxicity. The use of vasoactive agents to redistribute arterial blood flow towards tumour, and of biodegradable microspheres to slow tumour blood flow, have also been suggested as methods of further improving tumour exposure to drug. We present 21 patients who received intrahepatic arterial chemotherapy for colorectal liver metastases. Combined treatment (angiotensin II, albumin microspheres and 5-fluorouracil) was administered 4–6 weekly, and bolus 5-fluorouracil was given in the intervening weeks. Toxicity was minimal. Responses were seen in seven patients. Fewer than half of the deaths were from liver metastases; a quarter of the patients died from non-cancer-related causes. Survival was prolonged in the treated group compared with historical controls. These results suggest that this regimen has activity in patients with colorectal liver metastases.
Duplex Doppler ultrasound has been used to make measurements of liver blood flow. The relationship between time average velocity as measured using pulsed Doppler and the true mean velocity was determined using a flow phantom. Correction factors were applied to measured time average velocities of blood in the hepatic artery and portal vein. Blood flow was calculated from the product of corrected velocities and the cross-sectional area of the vessels. There was no significant difference in total liver blood flow for patients with colorectal liver metastases when compared with controls. However, the ratio of the hepatic arterial flow to the sum of the portal and hepatic arterial flows (Doppler perfusion index, DPI) was markedly elevated (P<0.0001) in the patients with metastases when compared with the controls. The DPI values for a third group of subjects who had undergone resection for colonic cancer but who had no proven liver metastases overlapped the values for the other two groups. When attention is paid to technique, the procedure can detect and quantify the changes in liver blood flow which occur in the presence of metastases.
A new radiotelemetry receiver type 7060 for use with radiopills is described. Its performance under laboratory conditions was assessed and its use for clinical colonic pressure measurements evaluated. The receiver, which resembles a small microcomputer, was easy to set up and worked reasonably well under ward conditions. Difficulties were experienced with the belt aerial supplied with the receiver, which did not reliably pick up signals from a freely moving radiopill. The receiver is not suitable for ambulatory applications. Its main clinical use is in situations where frequent sampling of the radiopill's signal over a long period of time is essential (e.g. colonic pressures). The large quantity of data generated can be fed from the receiver's analogue or digital output on line to a recorder.
The effect of ispaghula husk on colonic motility of the right and left side was examined in 10 patients with left sided diverticular disease using an untethered pressure sensitive radiotelemetry capsule. After treatment, ispaghula husk reduced mouth to rectum transit by a median of 8.8 hours and the time to midtransverse colon by five hours. In the right colon there was an increase in the median percentage activity of 7% and the median number of pressure waves greater than 5 mm Hg/hour rose by 35.3. Motility changes in the left colon were less pronounced. Five of the seven patients with abdominal pain and six of the nine patients with altered bowel habit responded to treatment. These results suggest that it is ispaghula husk9s action on the right unaffected colon which alleviates the symptoms of left sided diverticular disease.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
