Biomedical subjects

David Waterhouse

Publications and source records attributed to David Waterhouse.

3 recordsLinked to original sources

PubMed2004

Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer.

PURPOSE: This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer. PATIENTS AND METHODS: Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry. RESULTS: Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18 months) was confirmed in eight patients (one breast, two colon, two pancreas, and three NSCLC patients). Treatment was well tolerated, with 81% of patients experiencing toxicities of grade 2 or less severity. Most common toxicities included diarrhea, nausea, asthenia, and rash. A mild association (P < .055) between baseline pERK expression in archived tumor specimens and SD was observed. CONCLUSION: CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

Administration, Oral↗

PubMed2004

Prostate implant evaluation using tumour control probability--the effect of input parameters.

In this paper, we examine the effect of treatment parameters in a model used to evaluate permanent prostate implants. The model considers the prostate to be composed of 12 sub-sections, each sub-section is assigned a cell density based on the probability of finding cancer foci in that sub-section. Wasted dose as a result of the dose rate from the implant falling below a level adequate to counteract repopulation was found to vary by 2-16% over the range of radiosensitivity and repopulation rates considered. Within the model, applied to five dose distributions, the uncertainty in the tumour control probability (TCP) values calculated for each sub-section as a result of differences in the model parameters, was found to be less than 12% in most cases for the good quality implants. The difference in TCP values was much larger for the poor quality implant. Substituting a heterogeneous distribution of alpha for a single mean value resulted in generally lower TCP values though introducing a cutoff value with a Gaussian distribution had a profound effect on the calculated values. Despite uncertainties in the parameters, the model was able to identify sub-sections at risk of local recurrence but as a result of these uncertainties, the TCP values can only be considered in the relative rather than absolute sense.

Brachytherapy↗

PubMed2004

Assessment of i-125 prostate implants by tumor bioeffect.

PURPOSE: A method of prostate implant dose distribution assessment using a bioeffect model that incorporates a distribution of tumor cell densities is demonstrated. This method provides both a quantitative method of describing implant quality and spatial information related to the location of underdosed regions of the prostate. This model, unlike any other, takes into account the likelihood of finding cancer cells in the underdosed region. METHODS AND MATERIAL: The prostate volumes of 5 patients were divided into multiple subsections and a unique cell density was assigned to each subsection. The assigned cell density was a function of probability of finding tumor foci in that subsection. The tumor control probability (TCP) for each subsection was then calculated to identify the location of any significantly underdosed part of the prostate. In addition, a single TCP value for the entire prostate was calculated to score the overall quality of the implant. RESULTS: Adequately dosed subsections scored TCP values greater than 0.80. The TCP for underdosed regions fell dramatically particularly in subsections at higher risk of containing tumor cells. CONCLUSIONS: Despite uncertainties in radiobiological parameters used to calculate the TCP and the distribution of cancer foci through the prostate, the bioeffect model was found to be useful in identifying regions of underdosed prostate that may be at risk of local recurrence due to inadequate dose. Unlike the isodose distribution, the model has the potential to demonstrate that small volumes of tissue underdosed in regions most likely to contain higher numbers of tumor cells may be more significant than larger volumes irradiated to a lower dose but with a lower probability of containing cancer cells.

Brachytherapy↗