David A. Van Echo

Physical aspects of yttrium-90 microsphere therapy for nonresectable hepatic tumors

Administration of yttrium-90 microspheres via the hepatic artery is an attractive approach to selectively deliver therapeutic doses of radiation to liver malignancies. This procedure allows delivering radiation absorbed doses in excess of 100 Gy to the tumors without significant liver toxicity. The microsphere therapy involves different specialties including medical oncology, radiation oncology, nuclear medicine, interventional radiology, medical physics, and radiation safety. We have treated 80 patients with nonresectable hepatic tumors with yttrium-90 microspheres during the past two years on an institutional study protocol. The nominal radiation absorbed dose to the tumor in this study was 150 Gy. Required activity was calculated based on the nominal radiation absorbed dose and patients liver volume obtained from the CT scan, assuming a uniform distribution of the microspheres within the liver. Microspheres were administered via a catheter placed into the hepatic artery. The actual radiation absorbed doses to tumors and normal liver tissue were calculated retrospectively based on the patients 99mTc-MAA study and CT scans. As expected, the activity uptake within the liver was found to be highly nonuniform and multifold tumor to nontumor uptake was observed. A partition model was used to calculate the radiation absorbed dose within each region. For a typical patient the calculated radiation absorbed doses to the tumor and liver were 402 and 118 Gy, respectively. The radiation safety procedure involves confinement of the source and proper disposal of the contaminated materials. The average exposure rates at 1 m from the patients and on contact just anterior to the liver were 6 and 135 uSv/h, respectively. The special physics and dosimetry protocol developed for this procedure is presented.

Renal failure and platinum pharmacokinetics in three patients treated with cis-diamminedichloroplatinum(II) and whole-body hyperthermia

SummaryThree patients with advanced refractory malignancies were treated with whole-body hyperthermia (WBH: 42–42.3° C) for 2 h during which time they also received an infusion of 60 or 80 mg/m2 of cis-diamminedichloroplatinum II (DDP). Each patient developed an elevated serum creatinine (2.7–13.6 mg/dl), with maximum creatinine occurring between days 7 and 12 after treatment. WBH did not alter plasma or urinary pharmacokinetics of total or ultrafilterable platinum compared with pharmacokinetic data of the same or other patients given DDP euthermically. Although the mechanism of the renal damage is unclear, it appears that WBH can potentiate the nephrotoxic actions of DDP and that further study of this combination is not warranted.

Cytoablative therapy with combined resection and cryosurgery for limited bilobar hepatic colorectal metastases

BACKGROUND Cryosurgery can be employed in patients with unresectable hepatic metastases when the tumor size and the number of metastases are limited. However, local recurrence can result from incomplete ablation. We proposed a trial of complete cytoablation with a combined approach of cryosurgery and hepatic resection for patients with bilobar hepatic metastases. METHODS Seven patients underwent cryosurgery alone (CRYO). Seven additional patients underwent combined resection and cryosurgery (CRYO+RES) for bilobar metastases. RESULTS In the CRYO group, 5 of 7 patients had at least one centrally located tumor. All 5 of these patients had early recurrence at the site of ablation. In the CRYO+RES group complete ablation was achieved in 7 of 7. Two (28.6%) of these patients developed local recurrence. CONCLUSION Cytoablation of hepatic metastases can be safely achieved with combined hepatic resection and cryosurgery in selected patients. Long-term survival data are necessary before advocating widespread application of this approach.

Approaches to optimal dosing of hexamethylene bisacetamide

SummaryHMBA is a potent differentiating agent capable of causing>95% morphological differentiation in cell lines in vitro. The induction of differentiation is dependent on both the concentration of and the duration of exposure to HMBA. However, acute toxicities (neurotoxicity and acidosis) have limited the maximal HMBAcss value to <2mm, which is at the lower limit of effective in vitro concentrations. When HMBAcss values have been maintained at 1–2mm, thrombocytopenia has limited the duration of HMBA infusion to ≤10 days. The present studies were performed to determine whether exposure to HMBA could be individualized and maximized without resulting in intolerable toxicity to patients and to determine which factors would predispose a patient to the development of acute toxicity during treatment with HMBA. For these investigations, patients were given HMBA at a targetcss using an adaptive-feedback-control method rather than at a set dose. Because HMBA administration produces large anion gaps, a simple maneuver such as alkalinization might enable the escalation of plasma HMBAcss values to >2mm. HMBA was given as a 5-day CI to 14 patients (26 courses) at 2 target HMBAcss levels near the maximal tolerated value in the presence or absence of concurrent alkalinization with sodium bicarbonate. Symptomatic acidosis occurred in one patient who did not receive bicarbonate. Neurotoxicity proved to be dose-limiting at the target HMBAcss value of 1.5–2.0mm in the absence of concurrent alkalinization and at acss level of >2mm, regardless of alkalinization. No neurotoxicity was seen at target HMBAcss values of 1.5–2.0mm in patients who did receive concurrent alkalinization. Alkalinization was not associated with any detectable changes in plasma HMBA metabolites. With the maximal tolerable 5-day HMBAcss having thus been defined at 1.5–2.0mm, we attempted to maximize exposure to HMBA by defining a tolerable duration of infusion. Individualization of the duration of HMBA infusion to a target nadir PLT was performed in patients who had received an initial 5-day CI of HMBA at acss 1.5–2.0mm along with concurrent alkalinization. The AUC achieved and the thrombocytopenia produced during this first course were used to predict the duration of infusion that each patient would subsequently tolerate (at an HMBAcss of 1–2mm) to achieve a nadir PLT of 75,000–100,000/μl. The observed percentage changes in PLT matched the predicted percentage change in PLT, with the mean error (ME) being −8.9%. For a better determination as to which factors may contribute to neurotoxicity or acidosis in patients receiving HMBA, 98 courses of HMBA given as 5- to 10-day CIs to 56 patients were analyzed (multifactorial logistic regression). An HMBA AUC value of >7.5mm x day, the use of any concomitant narcotic analgesics, and a mean plasma HMBA level of >1.5mm or a peak plasma concentration of ≥1.75mm correlated significantly with grade 3 neurotoxicity (P<0.001), whereas concomitant alkalinization and a mean plasma HMBA concentration of <1.5mm were associated with a lack of neurotoxicity (P<0.001). An AUC value of >7.5mm x day, a mean or peak plasma HMBA level of >1.5mm, and an age of >70 years correlated with the likelihood of a large anion gap (P<0.03). With the above factors being accounted for, neither the duration of infusion nor theCcr value showed any correlation with these toxicities in this patient population. These results imply that HMBA may be given for individualized durations at acss of 1.5mm in the presence or absence of concomitant alkalinization and that narcotic analgesics should not be given to patients receiving this agent. However, due to the resultant acute neurotoxicity, it is unlikely that AUCs of >7.5mm x day will be tolerated during simultaneous maintenance of acss value of >1.0mm.

An Exploration of Relative Health Stock in Advanced Cancer Patients

Objective. The authors sought to empirically test whether relative health stock, a measure of patients’ sense of loss in their health due to illness, influences the treatment decisions of patients facing life-threatening conditions. Specifically, they estimated the effect of relative health stock on advanced cancer patients’ decisions to participate in phase I clinical trials. Method. A multicenter study was conducted to survey 328 advanced cancer patients who were offered the opportunity to participate in phase I trials. The authors asked patients to estimate the probabilities of therapeutic benefits and toxicity, their relative health stock, risk preference, and the importance of quality of life. Results. Controlling for health-related quality of life, an increase in relative health stock by 10 percentage points reduced the odds of choosing to participate in a phase I trial by 16% (odds ratio = 0.84, 95% confidence interval = 0.72, 0.97). Conclusion. Relative health stock affects advanced cancer patients’ treatment decisions.

Clinical pharmacology of cytarabine in patients with acute myeloid leukemia: a Cancer and Leukemia Group B study

The pharmacokinetics of cytarabine (ara-C) were determined in 265 patients with acute myeloid leukemia (AML) receiving ara-C (200 mg/m2 per day for 7 days as a continuous infusion) and daunorubicin during induction therapy. The mean (standard deviation) ara-C concentration at steady-state (Css) and systemic clearance (Cl) were 0.30 (0.13) μM and 134 (71) l/h per m2 respectively. Males had a significantly faster ara-C Cl (139 vs 131 l/h per m2,P=0.025) than females. Significant correlations were noted between ara-C Cl and the pretreatment, peripheral white blood cell count (P=0.005) and pretreatment blast count (P=0.020). No significant differences in ara-C Css or Cl were noted in patients achieving complete remission compared with those failing therapy (P=0.315,P=0.344, respectively). No significant correlations were observed between ara-C pharmacokinetic parameters and several indices of patient toxicity. Our findings indicate that variability in ara-C disposition in plasma at this dosage level does not correlate with remission status or toxicity in patients with AML receiving initial induction therapy with ara-C and daunorubicin.

The predictive and therapeutic value of thymidine phosphorylase and dihydropyrimidine dehydrogenase in capecitabine (Xeloda)-based chemotherapy for head and neck cancer†

To evaluate whether two molecular biomarkers, thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), could be clinically useful in predicting and improving the chemotherapeutic outcome of the oral fluoropyrimidine capecitabine (5′‐DFUR or Xeloda®), in the treatment of human head and neck squamous cell carcinoma (HNSCC).

Plasma kinetics of aclacinomycin A and its major metabolites in man.

SummaryThe plasma pharmacokinetics of the antineoplastic anthracycline antibiotic aclacinomycin A (Acm) and its metabolites were studied in 12 patients treated with 60–120 mg/m2 during a phase I clinical trial. Total plasma drug fluorescence initially declined very rapidly, but from 2 to 24 h after injection, fluorescence rose progressively to intensities greater than those measured 1 min after Acm injection. Plasma total drug fluorescence slowly declined from 24 to 72 hours after Acm administration. These events reflected the rapid disappearance of Acm and the subsequent appearance of two highly fluorescent metabolites. One metabolite co-chromatographed with and had a fluorescence spectrum identical to known metabolite F1 (bisanhydroaklavinone). The other metabolite did not co-chromatograph with any previously described Acm metabolite. This metabolite had a fluorescence spectrum unlike any previously described Acm metabolite and was not altered by treatment for 60 min with 0.2N HCl at 100°C or by treatment for 24h at 37°C with bacterial β-glucuronidase or limpet aryl sulfatase.

A phase II trail of vindesine in patients with refractory small-cell carcinoma of the lung.

A phase II study of vindesine at a dose of 3 mg/m2 I.V. for 6 weeks and every other week thereafter was carried out in 18 patients with small-cell carcinoma of the lung. All patients were refractory to conventional therapy and all had been treated previously with spindle inhibitors, vincristine, or VP 16-213. All patients were evaluable for response and toxicity. No objective responses were observed. Leukopenia, the only hematologic toxicity, occurred in 13 patients (72%). Neurotoxicity occurred in five patients (28%). Vindesine appears to have limited activity in patients with small-cell carcinoma of the lung previously treated with spindle inhibitors.

Doxorubicin plus VP-16-213 for the treatment of refractory breast carcinoma.

Thirty patients with refractory advanced breast cancer who had no prior treatment with doxorubicin or VP-16-213 received doxorubicin 45 mg/m2 I.V. on day 1 and VP-16-213 50 mg/m2 I.V. on days 1 through 5. Courses were repeated every 21 days when hematologic recovery permitted. Among 30 evaluable patients, one had a complete response and 11 had a partial response. Four patients had stabilization of their disease. There was thus a 40% response rate with a median response duration of 146 days (range 35-540). Toxicity included moderate to severe myelosuppression, infections, hemorrhage, and mucositis. In these poor prognoses in previously treated patients, the combination of doxorubicin and VP-16-213 appears to be an effective secondary treatment for metastatic breast cancer.