Using scenarios to explain life expectancy in advanced cancer: attitudes of people with a cancer experience.

PURPOSE: We sought the attitudes of people with a cancer experience to using best case, worst case, and typical scenarios for survival to explain life expectancy. METHODS: Oncology clinic attendees and Breast Cancer Network Australia (BCNA) members completed a survey describing two formats for explaining life expectancy to a hypothetical patient with advanced cancer-providing either three scenarios for survival or just the median survival time. RESULTS: Characteristics of the 505 respondents from outpatient clinics (n = 251) and BCNA (n = 254) were median age of 58 years, female 74 %, and breast primary 64 %. More respondents agreed that explaining three scenarios (vs. median survival) would make sense (93 vs. 75 %), be helpful (93 vs. 69 %), convey hope (68 vs. 44 %), and reassure (60 vs. 40 %), while fewer respondents agreed that explaining three scenarios (vs. median survival) would upset people (24 vs. 36 %); all p values < 0.001. Most respondents agreed that each scenario should be presented: best case 89 %, worst case 82 %, and typical 92 %. For information about their own prognosis, 88 % preferred all three scenarios and 5 % a single estimate of the median. Respondents with higher education were more likely to agree that presenting three scenarios would be helpful (95 vs. 90 %, p = 0.05). Respondents with breast cancer were more likely to agree that explaining three scenarios would upset people (31 vs. 13 %, p < 0.001). CONCLUSIONS: Most respondents judged presentation of best case, worst case, and typical scenarios preferable and more helpful and reassuring than presentation of just the median survival time when explaining life expectancy to patients with advanced cancer.

Randomized cross-over trial comparing inpatient and outpatient administration of high-dose cisplatin.

BACKGROUND/AIMS: Treatment with high-dose cisplatin (HDC) previously required inpatient (IP) admission with overnight hospitalization, but recently practice has shifted to outpatient (OP) therapy. We aimed to determine whether it is preferable to give HDC as an IP or OP using a two-period cross-over trial. METHODS: Eligible patients were starting chemotherapy with ≥2 cycles of HDC (≥100 mg/dose) and were suitable for OP treatment. All patients received an IP cycle and OP cycle: the order was randomly allocated. Pre-hydration, anti-emetics and chemotherapy were identical for IP and OP. Post-hydration varied by group (3 L normal saline (NS) for IP, 2 L NS for OP). The primary outcome was patient preference for IP versus OP treatment. Secondary outcomes included aspects of health-related quality of life, adverse events (dose delays and reductions, elevated creatinine and unplanned readmissions) and resource use. RESULTS: Fifty-nine patients were randomized, 53 completed two cycles of HDC. Most patients preferred OP treatment (36 vs 13, P = 0.002). There were no significant differences in patients' ratings of nausea, vomiting, fatigue, anxiety, depression or overall quality of life. Adverse events were few and unrelated to IP versus OP treatment. Nursing time was longer for IP than OP (163 vs 104 min, P < 0.001). CONCLUSION: OP treatment was preferred by most patients, appeared safe and used less resources.

Optimizing the erythromycin breath test for use in cancer patients.

The erythromycin breath test (EBT) is a putative in vivo probe for drug metabolism by cytochrome P450 3A4 (CYP3A4). Because many anticancer drugs are metabolized by this system, we sought to further develop the EBT as a tool for predicting the clearance, in cancer patients, of drugs metabolized by CYP3A4. Sixteen adult patients with incurable cancer were studied. The EBT was performed on day 1 and breath sampled after the i.v. injection of 4 microCi of 14C-erythromycin. The breath 14CO2 flux (CERt) was estimated at 11 time points over 2 h. On day 2, the EBT was repeated midway through a 10-min infusion of 100 mg of erythromycin lactobionate, and the plasma pharmacokinetics of erythromycin were determined. The infusion of 100 mg of erythromycin did not modify the EBT results significantly. The values of the conventional EBT parameter CER20 min obtained on day 1 were comparable for most subjects (0.03-0.06% dose/min), with the exception of an individual receiving the known CYP3A4 inducers dexamethasone and phenytoin who returned a value of 0.14% dose/min. There was no significant correlation between any of the conventional EBT parameters and erythromycin clearance. However, two parameters reflecting early emergence of breath radioactivity (1/TMAX and CER3 min/CERMAX) correlated significantly with erythromycin clearance (P = 0.005 and 0.006, respectively). Novel parameters derived from the EBT are significantly correlated with the clearance of erythromycin even in the presence of confounding factors, such as metastatic liver disease, altered protein binding, and comedication. These parameters may enable dose optimization of cytotoxics metabolized by CYP3A4.

Mechanisms of drug resistance to the platinum complex ZD0473 in ovarian cancer cell lines.

Acquired drug resistance to the sterically hindered platinum drug ZD0473 (formerly known as JM473 and AMD473) and currently being tested in phase I clinical trials, has been studied in two human ovarian carcinoma cell lines (CH1 and A2780) where previously, acquired cisplatin resistance has been described. Common mechanisms of resistance were observed in A2780 acquired cisplatin and ZD0473R (resistant) lines (including reduced drug transport and DNA platination, increased glutathione (GSH) and loss of the MLH1 DNA mismatch repair gene). However, contrasting mechanisms were observed in the CH1 sublines. While ZD0473 retained activity against the acquired cisplatin resistant sublines, cisplatin did not circumvent acquired ZD0473 resistance. The trans platinum complex JM335 circumvented resistance in CH1cisR and A2780ZD0473R lines, but not in A2780cisR or CH1ZD0473R cells. Overexpression of metallothionein (MT) in A2780 cells by stable gene transfection resulted in protection from the growth-inhibitory effects of cadmium chloride (3. 8-fold) and a range in protection with platinum drugs (from 7-fold with cisplatin, but only 1.3-fold with ZD0473). Overall, the results show that some mechanisms of resistance to ZD0473 are shared with those previously described in the same parental lines for cisplatin (e.g. in A2780), but in the CH1 lines, differing mechanisms were apparent. Moreover, ZD0473 possesses distinct cellular pharmacological properties in comparison with cisplatin with respect to reduced interactions with MTs, a thiol-containing species associated with tumour resistance to cisplatin.

Clinical and preclinical pharmacokinetics of raltitrexed.

Raltitrexed is a specific, folate-based inhibitor of thymidylate synthase with activity in advanced colorectal cancer comparable with that of fluorouracil (5-fluorouracil) plus folinic acid. Its activity is enhanced by rapid cellular entry and polyglutamation, with the polyglutamated derivatives having approximately 100-fold greater inhibitory potency than the parent compound. A number of phase I/pharmacokinetic studies have been performed, including schedules involving a 15-minute infusion every 3 weeks, weekly x 6 every 8 weeks, and every 2 weeks. The maximum tolerated dose (MTD) for the 3-weekly schedule was 3.5 to 4.5 mg/m2 in adults and 6 mg/m2 in a paediatric population. The MTDs for the other schedules have not yet been reported. The disposition of raltitrexed in patients is best described by a 3-compartment model with a terminal half-life (t1/2gamma) of 260 hours, the latter being subject to significant interpatient variability. A similar protracted t1/2gamma has been detected in all of the animal species studied. Together with evidence from the mass-balance studies performed, this delayed elimination suggests considerable sequestration of raltitrexed in tissues, predominantly as polyglutamate forms. Nevertheless, there has been no pharmacokinetic evidence of drug accumulation in plasma following repeated administration. On the basis of animal experiments, the oral bioavailability and penetration of raltitrexed into cerebrospinal fluid are both likely to be limited in the clinical setting. Raltitrexed is over 90% bound to plasma protein over the concentration range of 20 to 100 micromol/L. Apart from poly-glutamation, raltitrexed does not appear to be metabolised to a significant extent, and most of the excreted drug (approximately 20% of the administered dose) is recovered unchanged in the urine within the first 24 hours post-administration. The average clearance of raltitrexed is 2.4 L/h (40 ml/min), and this value is significantly reduced in patients with compromised renal function (glomerular filtration rate of 25 to 65 ml/min). These patients are more likely to experience severe antiproliferative toxicity with raltitrexed. A careful evaluation of renal function, particularly in the elderly, is warranted. It has not been possible to establish strong correlations between the plasma pharmacokinetics of raltitrexed and toxicity, and the cellular pharmacokinetics of raltitrexed may be more predictive. Studies in mice have demonstrated that delayed administration of folinic acid can assist in the recovery of animals from antiproliferative toxicity, possibly by promoting the release of polyglutamated drug from tissues. This approach should be evaluated as a rescue regimen in patients with severe proliferative toxicity.

Mini-review: discovery and development of platinum complexes designed to circumvent cisplatin resistance.

The discovery and development of new platinum-containing anticancer drugs have represented an integral part of anticancer drug development at the Institute of Cancer Research, Sutton, over almost 20 years. As part of a collaboration with chemists at Johnson Matthey, later AnorMED, four major new classes of platinum drug have been discovered, three of which have entered clinical trial. Earlier studies led to the clinical development of the less toxic analogue carboplatin and JM216, the first orally administerable platinum drug. In recent years, the focus has been on two lead complexes designed to overcome the major mechanisms of tumour resistance to cisplatin: JM335 (trans-ammine (cyclohexylaminedichlorodihydroxo) platinum(IV)), an active trans platinum complex; and ZD0473 (cis-amminedichloro(2-methylpyridine) platinum(II)), a sterically hindered complex shown to be less reactive towards thiol-containing molecules than cisplatin. JM335 shows some circumvention of acquired cisplatin resistance in vitro and exhibits unique cellular pharmacological properties in comparison to cisplatin or its cis-isomer in terms gene-specific repair of adducts on DNA and the rate of induction of apoptosis. ZD0473 is now in phase I clinical trial. Myelosuppression is the dose-limiting toxicity at a dose of 130 mg/m2 given i.v. every 3 weeks and there has been evidence of antitumour activity. ZD0473-resistant human ovarian carcinoma cell lines have been established in vitro. Some mechanisms of resistance common to those described for cisplatin (decreased drug uptake, increased glutathione) have been observed plus, in one cell line, increased BCL2 levels and loss of the DNA mismatch repair protein MLH1.

Bcl-2 family immunohistochemistry.

In recent years, immunohistochemistry as applied to the Bcl-2 family of proteins has represented a burgeoning area of interest to cancer researchers. The majority of studies have focused on the original member Bcl-2, first identified via its involvement in the common t(14;18) chromosomal translocation in B-cell lymphomas (1). However, since this discovery, preclinical and clinical interest in Bcl-2 has dramatically increased owing to (a) its recognition as the first of a new class of oncogene able to prolong survival by inhibiting programmed cell death (apoptosis) and (b) the discovery of many additional related genes/proteins some of which, like Bcl-2, inhibit apoptosis, whereas others, such as Bax, conversely promote cell death (2) (Table 1). Table 1 Bcl-2 Family Members Pro-apoptotic Anti-apoptotic Bax Bcl-2 Bcl-Xs Bcl-Xl Bak Bcl-w Bad Bfl-1 Bid Brag-1 Bik Mcl-1 Hrk A1.

Disarming the guarded prognosis: predicting survival in newly referred patients with incurable cancer.

People affected by cancer want information about their prognosis but clinicians have trouble estimating and talking about it. We sought to determine the nature and accuracy of medical oncologists' estimates of life expectancy in newly referred patients with incurable cancer. With reference to each patient, medical oncologists estimated how long they thought 90, 50, and 10% of similar patients would live. These proportions were chosen to reflect worst case, predicted, and best case scenarios suitable for discussions. After a median follow-up of 35 months, 86 of the 102 patients had died with an observed median survival of 12 months. Oncologists' estimates of each patient's worst case, predicted and best case scenarios were well-calibrated: 10% of patients lived for fewer months than estimated for the worst 10% of similar patients; 50% lived for at least as long as estimated for 50% of similar patients (predicted survival), and 17% lived for more months than estimated for the best 10% of similar patients. Oncologists' estimates of each patient's predicted survival were imprecise: 29% were within 0.67-1.33 times the patient's actual survival, 35% were too optimistic (>1.33 times the actual survival), and 39% were too pessimistic (<0.67 times the actual survival). The proportions of patients with actual survival times bounded by simple multiples of their predicted survival were as follows: 61% between half to double their predicted, 6% at least three to four times their predicted, and 4% no more than 1/6 of their predicted; similar to the proportions in an exponential distribution (about 50%, 10% and 10% respectively). Ranges based on simple multiples of the predicted survival time appropriately convey prognosis and its uncertainty in newly referred people with incurable cancer.

Cigarette smoking and duodenal ulcer.

Tobacco smoking delays healing of gastric ulcer and may influence duodenal ulceration. Seventy men, all cigarette smokers, were found to have duodenal ulceration at endoscopy. All were advised to stop smoking and received a three-month course of cimetidine. Endoscopy was repeated at three months (n = 63) and at six months (n = 56). At three months most (79%) patients showed ulcer healing and there was no difference between men who had and had not stopped smoking. At six months, however, a higher proportion (61% vs 28%, p less than 0.05) of smokers (n = 38) than ex-smokers (n = 18) had duodenal ulceration. This difference reflected a combination of increased ulcer persistence and ulcer relapse. Neither cimetidine nor cigarette smoking nor ulcer healing appeared substantially to affect duodenitis and fixed deformity. We conclude that continued cigarette smoking does not prevent the powerful duodenal ulcer healing effect of cimetidine but does predispose to an increased expectation of duodenal ulceration soon after cimetidine has been stopped.

Thrombocytopenia in malaria with immunoglobulin (IgM) changes.

Of 33 cases of naturally occurring human malaria 32 were found to have significant thrombocytopenia. Only one patient showed signs of bleeding. The lowest platelet levels were found between the day of diagnosis and the fourth day of treatment. Thereafter they returned to normal values. No other factors could be found to correlate with the presence or depth of thrombocytopenia, and no evidence of intravascular coagulation was found in any case. A rise in the immunoglobulin IgM was found in all 13 cases in which it was estimated. Since thrombocytopenia can occur independently of intravascular coagulation the latter should be diagnosed and heparin given only after clotting factors have been shown to be depleted.

BCL-2 family protein expression and platinum drug resistance in ovarian carcinoma.

The expression of the BCL-2 family proteins, BCL-2, BAX, BCL(XL) and BAK have been determined in a panel of 12 human ovarian carcinoma cell lines encompassing a wide range in sensitivity to cisplatin. Whereas BAX, BCL(XL) and BAK levels did not correlate with sensitivity, there was a statistically significant inverse correlation (r = -0.81; P = 0.002) between growth inhibition by cisplatin and BCL-2 levels. In sublines possessing acquired resistance to various platinum-based drugs or across a panel of human ovarian carcinoma xenografts, there was no consistent pattern of BCL-2 expression. Two relatively sensitive lines (A2780 and CH1) have been stably transfected with bcl-2 and bcl(XL) respectively and two relatively resistant lines (A2780cisR and SKOV-3) stably transfected with bax. Overexpression of BCL-2 in A2780 cells led to resistance to cisplatin compared to the vector control when assayed at 48 h post-drug incubation but a significant increase in sensitivity at 96 h. Relative rates of apoptosis at 48- and 96-h post-cisplatin exposure mirrored the growth inhibition. There was no significant difference in sensitivity of the pair of lines by clonogenic assay. No significant changes in chemosensitivity to a variety of DNA-damaging or tubulin-interactive agents were observed in the remaining transfected lines. Taken together, these results suggest that, in human ovarian carcinoma cells, high BCL-2 levels (either naturally occurring or through gene transfection) confers a trend towards sensitivity not resistance to platinum drugs.

A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug.

An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 microCi of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86-104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71-95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69-7.0) was collected in the feces. Over a collection period of 24-48 h, a total of 84.2% (range 80-95) was recovered in the urine as the sum of the parent drug and measured metabolites (5'-DFCR, 5'-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25-1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.