Michael P. Thirlwell

Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients.

Twenty‐three adult patients with chronic pain due to cancer completed a double‐blind, randomized, two‐phase crossover trial comparing plasma morphine concentrations and analgesic efficacy of oral morphine sulfate solution (MSS) and controlled‐release morphine sulfate tablets (MS Contin [MSC], Purdue Frederick, Inc., Toronto, Ontario, Canada). MS Contin was given every 12 hours to all patients except those whose daily morphine dose could not be equally divided into two 12‐hour doses with the tablet strengths available. MSS was given every 4 hours. Patients received both of the test drugs for at least 5 days, and, on the final day of each phase, peripheral venous blood samples for morphine analysis were obtained. Eighteen patients received MSC every 12 hours, and five received it every 8 hours. The same total daily morphine dose was given in both phases. In the 18 patients who received MSC every 12 hours, the daily morphine dose was 183.9 ± 140.0 mg (mean ± SD). In this group, the mean area under the curve (AUC) with MSC was 443.6 ± 348.4 ng/ml/hour, compared with 406.8 ± 259.7 ng/ml/hour for MSS (P > 0.20). Mean maximum morphine concentrations (Cmax) for MSC and MSS were 67.9 ± 42.1 and 58.8 ± 30.3 ng/ml, respectively (P > 0.05). Mean minimum morphine concentrations (Cmin) were 17.0 ± 17.7 and 18.3 ± 15.0, respectively (P > 0.30). There was a significant difference (P < 0.001) between the two drugs in time required to reach maximum morphine concentration (Tmsx). Mean Tmax after MSC occurred at 3.6 ± 2.3 hours. After MSS, it occurred at 1.3 ± 0.4 hours. In the five patients who received MSC every 8 hours, the findings paralleled those in the principal group, with no significant differences between MSC and MSS in Cmax or Cmin. and a highly significant difference between the two in Tmax. However, in this small group of patients, the AUC with MSC was significantly (P = 0.04) greater than that with MSS. All patients had very good pain control throughout the study and both formulations were well tolerated. There were no significant differences between MSC and MSS in pain scores or side effects. Under the conditions of this study there was no clinically significant difference in bioavailability between MSC and oral MSS. When given on a 12‐hourly basis in individually titrated doses, the MSC provided therapeutic plasma morphine concentrations throughout the dosing interval.

Comparative clinical efficacy and safety of immediate release and controlled release hydromorphone for chronic severe cancer pain

Background. The short elimination half‐life of hydromorphone necessitates 4‐hourly dosing to maintain optimal levels of analgesia in patients with chronic cancer pain. The purpose of this study was to compare the clinical efficacy and safety of controlled release hydromorphone administered every 12 hours and immediate release hydromorphone administered every 4 hours in patients with chronic severe cancer pain.

Steady‐State Pharmacokinetics of Hydromorphone and Hydromorphone‐3‐Glucuronide in Cancer Patients After Immediate and Controlled‐Release Hydromorphone

Although the pharmacokinetics of oral hydromorphone has been evaluated in healthy volunteers after small single oral doses, data are not available regarding the disposition of hydromorphone and its principal metabolite, hydromorphone‐3‐glucuronide (H3G), at steady‐state and after large oral doses. The authors studied the pharmacokinetics of hydromorphone and H3G after oral administration of an immediate‐release (IR) and controlled‐release (CR) formulation of hydromorphone at a daily dose of 48 ± 11 mg (range 6–216 mg) in a randomized, double‐blind, steady‐state, two‐way crossover evaluation in 18 patients with chronic cancer pain. Controlled‐release hydromorphone demonstrated equivalent bioavailability and acceptable CR characteristics, when compared with IR hydromorphone (CR vs. IR: AUC0–12 123.10 ± 20.38 vs. 118.98 ± 20.92 ng · hr · mL−1, P = NS, Cmax 17.76 ± 3.07 vs. 19.70 ± 4.04 ng · mL−1, P = N.S., Cmin 6.04 ± 1.01 vs. 5.28 ± 1.00 ng · mL−1, P = NS, and Tmax 4.78 ± 0.78 vs. 1.47 ± 0.22 hr, P = 0.0008). A significant linear relationship existed between hydromorphone dose and hydromorphone AUC (r = 0.8315, P = 0.0001) and between hydromorphone AUC and H3G AUC (r = 0.8048, P = 0.0001) over a wide dose range. The steady‐state molar ratio of H3G to hydromorphone was 27:1. The authors conclude that CR hydromorphone provides a pharmacokinetic profile consistent with 12 hourly dosing and that at steady state, oral hydromorphone is extensively metabolized to H3G, although the pharmacologic activity of this metabolite remains unknown.

The Diagnostic Value of CA 27-29, CA 15-3, Mucin-Like Carcinoma Antigen, Carcinoembryonic Antigen and CA 19-9 in Breast and Gastrointestinal Malignancies

In the past decade, considerable interest has arisen for defining the role of various tumor markers in the diagnosis of cancer. This cross-sectional study evaluates four breast cancer markers (CA 27-29, CA 15-3, MCA and CEA) and two gastrointestinal (GI) markers (CA 19-9 and CEA) in 213 patients. Receiver operating curves (ROC) revealed a sensitivity for the 90% specificity cutoff for breast cancers compared to breast benign diseases of 70% for CA 27-29, 67.5% for CA 15-3, 52.5% for MCA and 40% for CEA. When GI tumors were compared to benign GI disease, the sensitivity for 90% specificity was 40.3% for CEA and 32.3% for CA 19-9. Comparison of breast cancer and GI malignancies with other malignancies leads to a marked shift of the ROC curve to the right and loss of specificity. Late stage for all breast and GI tumor markers was found to be a predictor of high serum antigen level (p < 0.001). The presence of liver metastases in breast cancer was associated with abnormal levels of CA 27-29 (p = 0.028). Pancreas adenocarcinomas had a higher CA 19-9 antigen level (p < 0.001) than other GI malignancies. CA 27-29 appears to be at least as sensitive and specific as CA 15-3 in patients with breast cancer. None of the above markers retain their specificity when compared with a control group consisting of other malignancies.

Ambulatory hepatic artery infusion chemotherapy for cancer of the liver

We have used continuous hepatic arterial infusion chemotherapy to treat 105 patients with cancer of the liver originating from colorectal, other gastrointestinal, and nongastrointestinal sites. The response rate seen in colorectal metastases was two to three times that expected for systemic chemotherapy. The median survival of responders of 16 months was significantly better then for nonresponders (6 months). The median duration of response was 9 months. The results for patients with other tumor types were less encouraging. Although minor problems developed in about 30 percent of the patients, major complications requiring removal of the catheter were not common. Expertise derived from managing many patients and a team approach, with a defined protocol for catheter care and follow-up, contributed to the success of the ambulatory program. However, the role of hepatic arterial infusion chemotherapy remains under debate. At the root of the controversy is the lack of randomized, controlled trials supporting the superiority of hepatic arterial infusion over systemic chemotherapy in the treatment of colorectal liver metastases. This and other issues, including the current liberal use of implanted infusion pumps, should be studied.

Abstract 1385: Molecular changes in breast tumors following bevacizumab-based treatment: Final analysis of a randomized neoadjuvant study of bevacizumab or placebo, followed by chemotherapy with or without bevacizumab, in patients with stage II or III breast cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Bevacizumab (bev) has been widely studied in breast cancer (BC), yet no randomized trial in BC has reported in vivo molecular effects of bev on human tumor tissue. We conducted a trial to evaluate the safety, clinical & molecular effects of neoadjuvant chemotherapy plus bev for locally advanced BC. Methods: 90 pts were randomized (2:1:2:1) to 1 of 4 arms: Arm A: TAC (docetaxel, T: 75 mg/m2, doxorubicin, A: 50 mg/m2, cyclophosphamide, C: 500 mg/m2) + low dose bev (7.5 mg/kg); Arm B: TAC + low dose placebo (P); Arm C: TAC + standard dose bev (15 mg/kg); Arm D: TAC + Std-P. A run-in cycle of bev or P was followed by 6 cycles of TAC plus P or bev. Tumor biopsies pre- and 7-10 days post-run-in with bev or P were taken. Unblinding occurred post surgery (Sx): Arms A/C received maintenance bev to complete 52 wks, Arms B/D received no further P. Eligible patients were females with >3 cm, HER2(-) BC. Endpoints included safety and pathologic complete response (pCR) in breast & lymph nodes. To assess the effects of VEGF pathway inhibition on tumor vasculature, PCR analysis using the fluidigm array platform was performed on RNA from the pre- and post-run in samples to evaluate expression of 67 genes known to play a defined role in VEGF signaling. Results: 28 pts were assigned to Arm A, 30 to Arm C, and 32 to Arms B/D. 12 pts came off Tx before surgery (Arm A:2, Arm C:6, Arms B/D:4) and 78 received all Tx, underwent Sx and are evaluable for pCR. Two pts (6%) in Arms B/D, 5 pts (18%) in Arm A and 10 pts (33%) in Arm C had wound healing complications. 17% of pts in Arm C had Gr 3 (N=4) or Gr 4 (N=1) heart failure, none in Arms A/B/D. The pCR rate in evaluable patients was 18% (14/78): 5 (19%) Arm A, 3 (13%) Arm C, 6 (21%) Arms B/D. 45 samples (20 from Arms B/D and 25 from bev arms) were included in the pair-wise analysis to identify 6 genes that were differentially expressed. Bev resulted in a decrease in expression of Dll4, Cox2, Fibronectin (FN_EIIIB), angiopoietin 2 (Angpt2) and ESM1. In addition, upregulation of the cytokine, stromal derived growth factor (SDF1) was observed. Notably, genes such as CD31 or VE-cadherin were not appreciably differentially expressed. Of the genes that were downregulated, Dll4 and Angpt2 represent genes enriched in endothelial tip cells, which guide the migration of newly formed blood vessels. The decrease in these genes likely represents the effect of bev on reducing immature, growing vasculature in the tumor. Conclusions: This trial enabled the clinical and molecular evaluation of breast cancer tumor tissue pre and post-bev. Clinically, bev was associated with more wound healing and heart failure events and similar pCR rates compared to P. Tumor expression analysis for genes in the angiogenesis pathway supports the preclinical hypothesis that bev may primarily target immature tumor vasculature. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1385. doi:1538-7445.AM2012-1385