Search

Background The Australian and New Zealand Germ Cell Trials Group conducted a multicenter randomized phase III trial in men with good-prognosis germ cell tumors of two standard chemotherapy regimens that contained bleomycin, etoposide, and cisplatin but differed in the scheduling and total dose of cisplatin, the total dose of bleomycin, and the scheduling and dose intensity of etoposide. The trial was stopped early at a median follow-up of 33 months after a planned interim analysis found a survival benefit for the more dose-intense regimen. The aim of this analysis was to determine if this survival benefit was maintained with long-term follow-up. Methods Between February 1994 and April 2000, 166 men with good-prognosis metastatic germ cell tumors defined by modified Memorial Sloan-Kettering criteria were randomly assigned to receive 3[B.sub.90][E.sub.500]P (three cycles, repeated every 21 days, of 30 kU bleomycin on days 1, 8, and 15; 100 mg/[m.sup.2] etoposide on days 1-5; and 20 mg/[m.sup.2] cisplatin on days 1-5; n = 83) or 4[B.sub.30][E.sub.360]P (four cycles, repeated every 21 days, of 30 kU bleomycin on day 1,120 mg/[m.sup.2] etoposide on days 1-3, and 100 mg/[m.sup.2] cisplatin on day 1; n = 83). Endpoints included overall survival, progression-free survival, and quality of life and side effects, which were assessed using the Spitzer Quality of Life Index and the GLQ-8, respectively, before random assignment and during and after treatment. All analyses were by intention to treat. All P values are two-sided. Results The median follow-up was 8.5 years. All but five survivors (3%) were followed up for at least 5 years. Overall survival remained better in those assigned to 3[B.sub.90][E.sub.500]P than in those assigned to 4[B.sub.30][E.sub.360]P (8-year survival: 92% vs 83%; hazard ratio of death = 0.38, 95% confidence interval = 0.15 to 0.97, P = .037). Progression-free survival favored 3[B.sub.90][E.sub.500]P but was not statistically significantly different between the treatment groups (8-year progression-free survival, 3[B.sub.90][E.sub.500]P vs 4[B.sub.30][E.sub.360]P: 86% vs 79%; hazard ratio of progression = 0.6, 95% confidence interval = 0.3 to 1.1, P= .15). At the end of treatment, average scores for most side effect scales favored 3[B.sub.90][E.sub.500]P. After the completion of treatment, average GLQ-8 scores for numbness (P = ,003) and hair loss (P = .04) and the Spitzer Quality of Life Index (P = .05) favored 3[B.sub.90][E.sub.500]P. Conclusion The survival benefit of 3[B.sub.90][E.sub.500]P over 4[B.sub.30][E.sub.360]P was maintained with long-term follow-up. DOI: 10.1093/jnci/djq245

The authors argue that, in order to provide the best care for cancer patients in Australia in the 21st century, it is necessary to develop a more systematic method to evaluate the outcomes of ongoing research. Among their suggestions is the need for explicit guidelines for research, based on independent evidence and monitored regularly through links to existing databases.

The study aims to determine whether a motivational interviewing intervention increased successful smoking cessation attempts of patients with cancer attending a South Australian public hospital, as compared with usual care. It concluded that future efforts to improve cessation in this patient group focused on the delivery of more direct methods for encouraging spouse cessation and support to the patient in quitting, and the use of bupropion as an adjunct to cessation.

The moderate benefits of infused paclitaxel in women with metastatic breast cancer are discussed. Administration and dosage of paclitaxel needs to be optimized in the future.

* Objective: To determine if filgrastim recombinant human methionyl granulocyte colony-stimulating factor) used in addition to standard inpatient antibiotic therapy accelerated recovery from infection associated with chemotherapy-induced neutropenia. * Design: Randomized, double-blind, placebo-controlled trial. * Setting: Hematology and oncology wards of four teaching hospitals. * Patients: 218 patients with cancer who had fever (temperature >38.2 [degrees] C and neutropenia (neutrophil count 11 days, 4th quartile) by half (relative risk, 2.1 [95% Cl, 1.1 to 4.1]; P = 0.02). In exploratory subset analyses, filgrastim appeared to provide the greatest benefit in patients with documented infection and in patients presenting with neutrophil counts of less than 0.1 x [10.sup.9]/L. * Conclusions: Filgrastim treatment used with antibiotics at the onset of febrile neutropenia in patients with cancer who have received chemotherapy accelerated neutrophil recovery and shortened the duration of febrile neutropenia., Filgrastim appears to reduce the duration of neutropenia with fever caused by chemotherapy. Neutropenia is a reduction in the number of white blood cells called neutrophils and is associated with bacterial infections that can lead to sepsis, a severe inflammatory response to infection. Filgrastim is a recombinant hematopoietic growth factor that promotes the formation of blood cells such as neutrophils. Of 216 cancer patients who developed neutropenia with fever after chemotherapy, 109 were treated with filgrastim and 107 received a placebo. All patients received antibiotics. Patients taking filgrastim had a median duration of neutropenia with fever of five days, compared to six days in the placebo group. Neutrophil recovery was accelerated in the filgrastim group. Sixty percent of all patients had documented evidence of infection. Infected patients taking filgrastim had a median of four days of neutropenia versus five days for those taking placebo.

Catherine, Princess of Wales, has announced that she is undergoing preventive chemotherapy for cancer. Preventive chemotherapy is given after the cancer has been removed to prevent it from returning. It can also be used before or after surgery or radiotherapy to prevent the primary cancer from coming back. The effectiveness of preventive therapy depends on the type of cancer and the type of chemotherapy used. Chemotherapy works by disrupting the DNA in cancer cells, but it also affects normal cells, leading to side effects such as low white blood cell count, mouth ulcers, nausea, and fatigue. Patients can usually resume normal activities within weeks of completing the courses of chemotherapy. [Extracted from the article]

The adverse health effects of asbestos which poses a threat to global health and recognised as human carcinogens, causing malignant mesothelioma, lung, laryngeal and ovarian cancers1 as well as the debilitating non-malignant diffuse lung disease, asbestosis, and pleural plaques are reviewed. Although use, import and export of asbestos and asbestos-containing materials is banned in Australia and 51 other countries there is no safe level guidelines maintained for the exposure to asbestos and no discernible threshold below which there is no risk of mesothelioma.

Prevention and control of cancer through affordable drugs, additional funds for research and early detection are some of the challenges facing the Australian government to prevent rather than cure.

The quality of medical school education in Australia is generally believed to be uniformly high but there is no national procedure for evaluating its results. A national exit examination can be a uniform standard for evaluating all the medical school graduates in Australia and also foreign graduates desiring to work in Australia, as it would help the medical curricula to grow to meet the needs of the society.

The frequency and management of anaemia in Australian adults with solid and haematological malignancies is evaluated. Anaemia is prevalent among Australian patients with cancer managed in hospital oncology units.

Oncologists and haematologists reported a number of capability, opportunity and motivation-related barriers to referring their cancer patients to psychosocial care, as well as openness to strategies to address them.Rates of referral of patients to psychosocial services are low in most cancer treatment centers, while rates of distress are high. The purpose of this study is to identify clinicians’ barriers to referring cancer patients to psychosocial services and strategies that could increase rates of referral. A purposive sampling method ensured data were gathered in two large public teaching hospitals from seven oncologists and five hematologists with varying levels of experience, of whom five were female. Data were collected using semistructured interviews guided by the Capability, Opportunity, Motivation and Behavior model (Michie S, Atkins L, West R. The Behaviour Change Wheel: A Guide to Designing Interventions. United Kingdom: Silverback Publishing; 2014.). This helped us to identify modifiable variables associated with referral likelihood and associated evidence-based strategies using the Behavior Change Wheel. Data were analyzed using Thematic Analysis. Barriers relating to capability, opportunity, and motivation to refer to psychosocial services were identified, including lack of knowledge of available services, how to refer to them, and the types of patients who would benefit. Other barriers included the following: lack of time to discuss and refer, convoluted referral pathways, long waiting times, and fear of patient reluctance due to stigma. Respondents identified numerous strategies for overcoming barriers, including training on referral best practice, role-plays, the provision of lists of services with referral and contact details, and increasing service capacity via additional funding. Findings inform the development of acceptable, evidence-based strategies, to improve rates of referral to psychosocial services by oncologists and hematologists. Without implementation, a substantial number of people affected by cancer will continue to suffer from potentially treatable distress.

The authors argue that growing research evidence on the link between obesity and cancer highlights the need for the Australian Government to enhance obesity control measures. They recommend that lessons learned from tobacco-control be applied to the development of a national obesity strategy that fosters healthier eating habits among people.

Zero-alcohol beverages containing 0.0-0.5% alcohol by volume may offer public health benefits if individuals use them to substitute for alcohol-containing products, thereby reducing alcohol use. There are, however, concerns that zero-alcohol beverages may encourage adolescents’ earlier interest in alcohol and increase exposure to alcohol company branding. As this poses a challenge for parents, we studied parents’ views on zero-alcohol beverages and their provision to adolescents.

The link between alcohol consumption and cancer is well established, but public awareness of the risk remains low. Mandated warning labels have been suggested as a way of ensuring "informed choice" about alcohol consumption. In this article we explore various ethical issues that may arise in connection with cancer warning labels on alcoholic beverages; in particular we highlight the potentially questionable autonomy of alcohol consumption decisions (either with or without labels) and consider the implications if the autonomy of drinking behavior is substantially compromised. Our discussion demonstrates the need for the various ethical issues to be considered and addressed in any decision to mandate cancer warning labels. [ABSTRACT FROM AUTHOR]

Leaving aside genetics and inheriting cancer-causing genes, your ethnicity and family lifestyle can alsoinfluence cancer risk. Although for some cancers such as lung, head and neck, andcervical cancer the incidence is higher in very remote andremote areas, the overall cancer risk is lower than otherareas when all cancers are combined. Parents' education level can influence health literacy- that is, their understanding of the health system andpublic health messages, the importance of prevention andscreening, and healthy lifestyles. [Extracted from the article]

This review updates the literature on hope and oncology following a prior review of studies up until 2009. It particularly focusses on the evolution of the definition of hope in the light of the clinical experience of patients with cancer, their carers and health professionals.

Rural cancer patients are often disadvantaged in access to psychological services. We reviewed remote counselling research for psychological support using telephone, videoconferencing, and the Internet as a potential solution. Telephone counselling is the most extensively researched, while there are encouraging findings in emerging research about videoconferencing and Internetbased psychological care. Where no face-to-face psychological service exists, these technologies are promising, yet unproven. Less variable methods are needed to better assess the technology and therapeutic approach for stronger evidence.

In reviewing the latest trials of antiemetic usage to prevent cytotoxic chemotherapy induced emesis, gaps in the literature suggest directions for future research and identify methodological approaches to be used in future investigations. The usage of molecular techniques and the identification of new receptors may allow new antiemetics to be developed and identification of the genes coding for antiemetic receptors may be used to select the appropriate antiemetics for individuals. Given the success achieved in controlling post chemotherapy vomiting, future studies should focus upon the control of nausea, and measure the impact of antiemetic control on quality of life as well as evaluating the pharmacoeconomics of these agents. Accounting for the interaction of antiemetics with cytotoxics becomes more important in trial design with the increasing complexity of antiemetic regimens. More information is needed on the emetic potential of the various combination chemotherapy regimens, multiple day chemotherapy and chemotherapy over multiple cycles. The emetic potential of prolonged administration of oral chemotherapy and newer biologicals and targeted therapies needs to be recorded. Further studies are required in specialized areas such as with high dose chemotherapy, for radiation induced emesis and in pediatrics.

Tumour hypoxia continues to remain one of the greatest challenges in the treatment of solid tumours. An important avenue to follow with both radiotherapy and chemotherapy is the development of hypoxic cytotoxins such as tirapazamine. The present review covers the history of tirapazamine from preclinical models to clinical trials. The biochemistry as well as the pharmacokinetics of this bioreductive agent are presented. Laboratory data demonstrating the enhanced effect of radiation and cisplatin when combined with tirapazamine are also discussed. There is considerable evidence supporting the potentiation of anti-tumour effect of cisplatin by tirapazamine. Several clinical trials for various tumour sites have been testing the synergistic effect of cisplatin-tirapazamine with and without radiotherapy. These are also reviewed in the present paper. The current literature data on tirapazamine leaves unanswered questions about its action and toxicity. While the current number of phase III trials limits comprehensive conclusions about the administration of this drug, there is a unanimous indication that further clinical studies are warranted.

Anticipatory nausea and vomiting (ANV) is not only a learned response but can occur without prior exposure to chemotherapy depending on patient emotional distress and expectations. The best method to avoid development or reinforcement of ANV is to avoid both vomiting and nausea from the first exposure to chemotherapy. If ANV develops, benzodiazepines have been documented to help in adult patients, and several psychological techniques are also of help, including systematic desensitization. The evidence on which these conclusions are based is reviewed in this article.

As many as 40–80% of patients undergoing radiotherapy (RT) will experience nausea and/or vomiting, depending on the site of irradiation. Fractionated RT may involve up to 40 fractions over a 6–8 weeks period, and prolonged symptoms of nausea and vomiting could affect quality of life. Furthermore, uncontrolled nausea and vomiting may result in patients delaying or refusing further radiotherapy. Nausea and vomiting are often underestimated by radiation oncologists. Incidence and severity of nausea and vomiting depend on RT-related factors (single and total dose, fractionation, irradiated volume, radiotherapy techniques) and patient-related factors (gender, general health of the patient, age, concurrent or recent chemotherapy, psychological state, tumor stage). Current antiemetic guidelines prescribe the emetogenicity of radiotherapy regimens and recommend the use of 5-HT 3 antagonists with or without a steroid for prophylaxis in moderately and highly emetogenic treatment (MASCC, ASCO, ASHP, NCCN). The new proposed guidelines summarise the updated data from the literature and take into consideration the existing guidelines. According to the irradiated area (the most frequently studied risk factor), the proposed guidelines are divided into four levels of emetogenic risk: high, moderate, low and minimal. They offer guidance to prescribing physicians for effective antiemetic therapies in RINV.

This paper uses an evidence-based approach whenever possible to formulate recommendations, emphasizing the results of controlled trials concerning the best use of antiemetic agents. We address issues of dose, schedule, and route of administration of five selective 5-HT3 antagonists. We conclude that for each of these five drugs, there is a plateau in therapeutic efficacy above which further dose escalation does not improve outcome. Furthermore, for all classes of antiemetic agents, a single dose is as effective as multiple doses or a continuous infusion. The oral route is as efficacious as the intravenous route of administration, even with chemotherapy of high emetic risk. Selective antagonists of the type 3 serotonin receptor (5-HT3) in combination with dexamethasone and aprepitant are the standard of care for the prevention of emesis following chemotherapy of high emetic risk.

This article examines how patients with cancer construct and legitimate do-not-resuscitate (DNR) orders. Semi-structured interviews with 23 outpatients attending an oncology clinic were tape-recorded, transcribed, and analyzed in accordance with discourse-analytic methodology. Results indicate some variability for participants regarding the meaning of DNR orders, which were nonetheless viewed as appropriate and desirable. The patient's subsequent death was legitimated primarily through the invocation of highly valorized discourses within Western society: nature, autonomy, and compassion. Non-compliance with DNR orders, or the instigation of CPR was seen as violating nature, infringing autonomy, and as uncompassionate. The combined effect was to construct dying as a natural event which is the concern of the individual patient and their family, endorsing medical non-intervention in the process. This research provides support, from the patients’ viewpoint, for a policy of non-intervention when death is imminent and inevitable, and for those questioning the wisdom of a default policy of initiating CPR on any hospitalized patient, especially those patients inevitably in the process of dying.

The videoconferencing link between the Royal Adelaide Hospital Cancer Centre in South Australia and the Royal Darwin Hospital in the Northern Territory was established to allow Darwin clinicians to discuss cases in multidisciplinary oncology meetings at the tertiary referral center. This was evaluated by questionnaires distributed to the 20 health professionals involved and a group of 8 patients with breast cancer whose case histories had been discussed via videoconferencing. All clinicians found the telemedicine link to be either useful or very useful in at least one aspect of their practice. The major benefit was cited as enabling remote area clinicians to participate in multidisciplinary cancer meetings. Three of the 5 remote clinicians who practiced solely in the Northern Territory found that the telemedicine consultation increased their workload, while only 2 of 13 clinicians who practiced solely in South Australia reported an increase over their normal activities, the others reporting no difference. Benefits identified included better support of isolated clinicians, decreased travel, and enhanced education and peer review. Perceived difficulties were technical problems, the impersonal nature of the interaction, inability to examine the remote patient and lack of reimbursement for the consultation. Seven of the eight patients surveyed were satisfied or very satisfied with the telemedicine consultation. Four patients wished to have access to videotape of the multidisciplinary meeting. Of those requiring travel for treatment, all believed that the telemedicine consultation influenced their care and shortened their time away from home.

Abstract:  To assess the Karnofsky Performance Status (KPS) scale and the Eastern Cooperative Oncology Group (ECOG) scale with respect to interobserver reliability and interobserver difference between the two scales, 100 consecutive patients in a medical oncology unit were assessed using both scales, which were then given to three independent raters and also to the patients themselves. There was a high level of agreement between most paired assessors. There were three exceptions, which were the RMO/patient and nurse/patient pairs on the KPS scale and the RMO/patient pair on the ECOG scale. The level of agreement was better on the ECOG scale. For individual raters there is no statistical difference between the ECOG and Karnofsky scales. There was good agreement between all raters for both scales. Interobserver variability was less using the ECOG scale. We conclude that either scale could be used with good interobserver reliability. The ECOG scale minimises differences between observers.

To assess the results and toxicity of a regimen of combined chemotherapy and radiotherapy for patients with non‐AIDS‐related primary central nervous system lymphoma. Prospective assessment of patients treated with Intravenous methotrexate followed by cranial irradiation between 1 January 1991 and 31 July 1995. Patients attending nine Australian and New Zealand centres who were eligible and gave informed consent. Probability of survival at two years, and acute toxicity. Twenty‐four patients were treated. Their probability of survival at two years was 70% (95% confidence interval [Cl], 45%‐95%). The acute toxicity of the regimen was minimal in most cases, but one patient died of treatment‐related neutropenia and subsequent sepsis. Two patients showed progression of pre‐existing short term memory disturbance, without evidence of recurrent lymphoma. Combined‐modality therapy improves survival in patients with non‐ AIDS‐related primary central nervous system lymphoma, at least In the short term, relative to radiotherapy alone. The combined regimen resulted in only moderate treatment‐related morbidity. Longer follow‐up is required for a more accurate estimate of late effects and long‐term survival prospects.

A total of 22 patients with superficial transitional cell carcinoma of the bladder, uncontrolled cystoscopically and unsuitable for or having failed intravesical therapy, received 50mg. oral methotrexate per week for 12 months. Of the patients 7 (32%) achieved or remained in complete remission and 5 achieved a partial response, while 4 remained stable, 3 had progression and 3 were not evaluable. Patients who were still alive had a median followup of 2.5 years. Two patients with complete remission had relapse at 16 and 26.4 months, and 5 were disease-free at 34.5, 31.3, 18.6, 17.8 and 16.8 months, respectively. The methotrexate was generally well tolerated but 2 patients discontinued therapy because of dyspnea (1 subsequently died of respiratory failure that was possibly related to the methotrexate) and 1 because of persistent grade 2 mucositis. Grade 3/4 toxicities occurred in 3 patients: 1 each with reversible increases in creatinine and aspartate aminotransferase, and 1 with gastric bloating. There was little hematological toxicity. Reversible skin lesions developed in 4 patients. This oral treatment may provide an effective alternative to intravesical therapy but can be associated with severe toxicity.

Toremifene is an antiestrogen that binds strongly to estrogen receptors (ER). A total of 19 previously treated postmenopausal women with metastatic breast cancer whose performance status was good and whose ER status was positive or unknown were studied to determine the maximum tolerated dose of toremifene. Cohorts of patients received 200, 300, or 400 mg/m2 p.o. daily until relapse or unacceptable toxicity had occurred. Nausea, vomiting, and dizziness were dose-related. Three of five patients receiving 400 mg/m2 experienced moderate or severe vomiting and another developed reversible disorientation and hallucinations. Mild sweating, peripheral edema, vaginal discharge, and hot flushes were encountered at all doses. Reversible corneal pigmentation was identified in seven cases but was not of clinical importance. The pharmacokinetics of toremifene was studied weekly and in detail on day 42 using a high-performance liquid chromatographic (HPLC) assay that identified the parent compound and three active metabolites,N-desmethyltoremifene, (deaminohydroxy)toremifene, and didemethyltoremifene. Steady state was achieved at 1–3 weeks. The toremifene area under the curve and the maximal concentration were dose-dependent at high doses. The recommended phase II dose is 300 mg/m2 p.o. daily.

This phase I study investigated flavone acetic acid (FAA) given as a 12-h intravenous infusion every 3 weeks in the absence of urinary alkalinisation. Cohorts of three patients were treated at doses of 7, 10 and 13 g/m2. One subject had colon cancer; 5, renal cancer; and 3, lung cancer. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in four patients, 1 in two subjects and 2 in three cases. The maximum tolerated dose was 13 g/m2. The dose-limiting toxicities were WHO grade 3 hypotension and grade 3 diarrhoea. Other toxicities included lethargy and dizziness, nausea, temperature fluctuation, myalgia and dry mouth, but no significant myelosuppression was encountered. One patient receiving 10 g/m2 for renal cancer showed a partial response that lasted for 3 months and included the resolution of pulmonary and cutaneous metastases. The pharmacokinetics showed large interpatient variability. At 12–16 h post-infusion, the plasma elimination profile entered a plateau phase, with frequent increases in concentration suggesting enterohepatic recycling. Neither peak FAA levels nor AUC values were dose-dependent at the doses studied. Peak plasma levels were 101–402 µg/ml and AUC (0–48 h) values were 75–470 mg ml-1 min. Plasma protein binding varied with total concentration. Two metabolites were detected in the plasma, and both also underwent apparent enterohepatic recycling. Repeat dosing resulted in decreases of up to 48% in peak levels and AUC values for FAA in three of six patients. Of the total FAA dose, 39%–77% was excreted in the urine as FAA or metabolites within 2 days. The dose recommended for further phase II studies is 10 g/m2.

(i) To assess the efficacy and tolerability of tropisetron when used for acute and delayed cisplatin‐induced emesis. (ii) To investigate whether dexamethasone added to tropisetron improves the control of emesis for patients who do not achieve a complete response to tropisetron alone. (iii) To assess sex of the patient and alcohol intake as prognostic factors for nausea and vomiting. A prospective open label phase II trial over one or two cycles of chemotherapy. Data collection was based on observed response and patients’ self‐reporting. Twenty Australian tertiary care hospitals in 1994. 102 male and female patients from 18 to 75 years with histologically confirmed malignancy receiving their first chemotherapy containing ≥50 mg/m2cisplatin. In Cycle 1 tropisetron 5 mg was given intravenously before chemotherapy on Day 1, then 5 mg orally before breakfast on Days 2 to 6. In Cycle 2, dexamethasone 20 mg intravenously on Day 1, then 8 mg orally on Days 2 to 6 could be added to tropisetron if a complete antiemetic response had not been achieved in Cycle 1. Number of vomiting episodes and severity of nausea for 6 days after chemotherapy; severity of side effects; patient satisfaction with chemotherapy treatment; oestradiol levels in women; and past alcohol consumption in men and women. (i) The complete response rate (CR) for acute emesis in Cycle 1 was 64% (95% confidence interval [CI], 54%–72%), with 84% (95% CI, 76%–90%) having ≤2 vomits. The CR for delayed emesis was 24% (95% CI, 17%–32%). The CR for acute nausea was 56% (95% CI, 47%–66%), with 97% (95% CI, 91%–99%) having ≤2 nausea episodes. The CR for delayed nausea was 21% (95% CI, 14%–30%). Seventy‐one patients received Cycle 2. The main side effects were headache (20 patients) and constipation (16 patients). The control of acute emesis was rated as “good” or “very good” by 68% of investigators; 85% rated the tolerability of treatment as “good” or “very good”. Treatment was rated as “very satisfactory” or “satisfactory” by 52% of patients. (ii) The CR for acute emesis with dexamethasone added was 78% (95% CI, 64%–88%). (iii) Women with lower oestradiol levels had better control of emesis, although this difference was not statistically significant. Chronic alcohol intake and binge drinking were strongly associated with a complete acute antiemetic response. Tropisetron was effective for acute cisplatin‐induced emesis; adding dexamethasone enhanced this response. Both single and combined therapy had less effect on delayed emesis. The impact of alcohol on control of emesis is a chronic rather than acute phenomenon which requires prospective testing.

A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m2 per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m2, three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m2, two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 µM. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m2 per day.

The efficacy and toxicity of 120 mg/m2 etoposide and 100 mg/m2 carboplatin given i.v. daily x 3 together with 750 mg/m2 cyclophosphamide and 14 mg/m2 vincristine given i.v. on day 1 (ECCO) in a regimen given every 28 days for 6 courses was assessed in 90 (40 limited stage, 50 extensive stage) previously untreated patients with small-cell lung cancer. Mediastinal irradiation using 50 Gy in 25 fractions was given to limitedstage patients without progression after 3 courses of chemotherapy. Cranial irradiation with 30 Gy in 10 fractions was given to all patients attaining a complete response (CR). Objective responses were seen in 83% [CR, 60%; partial response (PR), 23%] of patients with limited and 76% (CR, 22%; PR, 54%) of those with extensive disease. The median relapse-free survival for objective responders with limited disease was 13.4 months, with a median of 8.0 months for extensive-stage patients. The median relapse-free survival for patients achieving a CR was 13.4 months, with a median of 7.8 months for those undergoing a PR. The median survival was 13.3 months for patients with limited disease, with a median of 9.6 months for those with extensive disease. The median survival following a CR was 18.2 months, with a median survival of 9.9 months for those showing a PR. The combination was well tolerated, with either no nausea or nausea only (WHO grade 0 or 1) in 56% of patients and minimal mucositis, renal toxicity, neurotoxicity or ototoxicity. Neutropenia measuring <1.0×109 WBC/l (WHO grade 3 or 4) was seen in 74% of patients, with two deaths due to infection occurring during neutropenia. Thrombocytopenia of <50×109 platelets/l (WHO grade 3 or 4) occurred in 24% of patients. ECCO is a new, active, welltolerated program for previously untreated patients with small-cell lung cancer.

Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) metabolism has been reported to be saturable and associated with a fall in clearance of the drug as the dose is increased. The aim of the present study was to determine the disposition of 5'-dFUR and 5-fluorouracil (5-FU) when 5'-dFUR was given as a 5-day infusion, with the infusion rate increased stepwise every 24 h. Measurement of plasma and urinary levels of 5'-dFUR and 5-FU at steadystate for each infusion rate enabled the estimation of 5'-dFUR renal (ClR) and nonrenal (ClNR) clearance and 5-FU renal clearance. A total of 28 patients with histologically proven malignancy received 5-day courses of 5'-dFUR ranging in dose from 3.75 to 20 g/m2 per 120 h. The lowest dose given over 24 h was 0.25 g/m2, and the highest was 5 g/m2. Steady-state plasma levels of 5'-dFUR ranged from 167 to 6.519 ng/ml. At these plasma levels there was no evidence of significant saturation of 5'-dFUR metabolism; steady-state plasma levels of 5'-dFUR increased approximately linearly with dose, and nonrenal clearance did not change significantly with dose. There was also no evidence of nonlinearity in 5'-dFUR renal clearance. The mean (±SD) ClR of 5'-dFUR was 108.9±53.6 ml/min per m2 (range, 45.7–210 ml/min per m2), and the ClNR was 728±181 ml/min per m2 (range, 444–1,119 ml/min per m2). Renal clearance comprised 13% of the total 5'-dFUR clearance. The mean renal clearance of 5-FU was 100.8±48.6 ml/min per m2 (range, 23.5–198 ml/min per m2). There was considerable interpatient variability in 5'-dFUR renal and nonrenal clearance, event at the same dose level. We concluded that the administration of 5'-dFUR by the infusion method described avoided the saturation of nonrenal elimination processes reported to occur with shorter infusion schedules.

The disposition of the cisplatin analogue carboplatin was studied in seven patients with small cell lung cancer. Carboplatin 100 mg/m2 was administered without hydration by a 1-h infusion with VP16-213 120 mg/m2 on days 1, 2 and 3 of each course. Plasma and urine collections were made on days 1 and 3 of the first course of treatment. Carboplatin levels in plasma ultrafiltrate and urine were quantitated using a specific and sensitive, highperformance liquid chromatographic assay which involved sample clean-up on a Dowex-2 column prior to injection. Estimates of pharmacokinetic parameters determined using either compartmental or non-compartmental methods were comparable. There was no difference between carboplatin pharmacolinetic parameters determined on days 1 and 3 of treatment. The mean (±SD) carboplatin half-life determined from plasma data on day 1 was 105±30.4 min and was not significantly different from that determined using urinary excretion rate data (107±51.7 min). Urinary excretion rate plots showed that carboplatin elimination was mono-exponential for up to 14 h after infusion. Totalbody clearance was 105±40.0 ml min-1 m-2, renal clearance 64.3±44.1 ml min-1 m-2, and volume of distribution 17.3±4.2 l/m2 on the 1st day of treatment. Of the administered dose, 58.4%±21.2% was recovered in urine over a 24-h period after the start of the infusion. The mean renal clearance of carboplatin was comparable to creatinine clearance. Carboplatin disposition was clearly defined in the patients studied using analytical methodology specific for the unchanged drug.

Trimetrexate (TMTX) is a potent inhibitor of dihydrofolate reductase that circumvents the transport resistance seen with methotrexate and has a wide spectrum of preclinical activity. A total of 18 patients with advanced cancer were treated in a clinical and pharmacological phase I trial with TMTX given as a continuous 5-day intravenous infusion. Neutropenia, thrombocytopenia and stomatitis were the dose-limiting toxicities at the maximum tolerated dose of 50 mg/m2 per 120 h (10 mg/m2 per day for 5 days). There was one septic death associated with neutropenia. Other toxicities were mild rash, mild nausea and transiently raised serum transminase levels. Significant relationships between the dose given and the AUC of plasma TMTX and the steady-state plasma level were established. Significant, although weak, relationships between the percentage of change in neutrophils and platelets and both the AUC and steady-state plasma level of TMTX were also observed. No objective tumour responses were seen, although six patients had stable disease. The recommended phase II dose for a continuous infusion of trimetrexate is 40 mg/m2 per 120 h.

Abstract: Various aspects of trial design and planning for clinical testing of antiemetic therapies administered to cancer patients are considered. It is generally felt that a randomized double-blind parallel-arm design is the best. Ways of achieving adequate power of such studies are discussed briefly, as is the need for previous identification of primary and secondary end-points. Finally, summary recommendations are given.

Abstract: The aim of the present study was to investigate whether cisplatin would enhance the radioresponse of a human tumour xenograft when given in different schedules combined with accelerated fractionated radiation therapy. A human squamous carcinoma of the hypopharynx, FaDu, was grown in the thigh of athymic nude mice. Tumours were exposed to twice-daily 2-Gy fractions, applied 6 h apart over 2 weeks, 5 days a week, alone or combined with cisplatin given at maximally tolerated doses in three different schedules: (1) i.p. as a single bolus (SB) or (2) i.p. as a daily bolus at 30 min before the first daily radiation fraction or (3) s.c. as a continuous infusion through a mini-osmotic pump over 13 days, commencing 24 h prior to the first daily radiation fraction. The end point for the study was tumour growth delay (TGD), calculated as the difference between the delay in regrowth to 200% of the initial tumour size in treated versus control mice. SB cisplatin plus radiation showed only an additive effect on TGD, whereas daily-bolus and continuous-infusion cisplatin demonstrated a greater than additive effect when combined with accelerated fractionated radiation in this human tumour model. Cisplatin appears to be especially beneficial as a radiation enhancer when given throughout the course of radiation.

Only a few studies have been carried out in children on the prevention of chemotherapy-induced acute emesis. 5-HT3 antagonists have been shown to be more efficacious and less toxic than metoclopramide, phenothiazines and cannabinoids. The optimal dose and scheduling of the 5-HT3 antagonists has not been identified. Combinations of a 5-HT3 antagonist and dexamethasone show increased efficacy with respect to 5-HT3 antagonists alone. All pediatric patients receiving chemotherapy of high or moderate emetogenic potential should receive a combination of a 5-HT3 antagonist and dexamethasone to prevent acute emesis. No studies have specifically evaluated antiemetic drugs in the prevention of chemotherapy-induced delayed and anticipatory emesis in children.

Accurate public perceptions on the risk factors associated with cancer are important in promoting primary, secondary, and tertiary prevention. Limited studies have explored this topic among patients with cancer in non-western, low-to-middle-income countries. A cross-sectional survey to compare Australian and Vietnamese cancer patients’ perceptions of what caused their cancer was undertaken. Adult, patients with cancer from both countries, receiving radiotherapy treatment completed a standardized survey, which included a 25-item module assessing their beliefs on the causes of their cancer. Items ranged from known evidence-based causes (eg, smoking, sun exposure) to non-evidence-based beliefs (eg, stress or anxiety, physical injury, or trauma). Country-specific logistic regression analyses were conducted to identify differences in the determinants of patients’ top perceived causes. A total of 585 patient surveys were completed (75% response rate; 285 from Australia, and 300 from Vietnam). Most patients were male (58%) and aged 60 years and older (55%). The most frequently reported risk factor overall and for the Australian sample was “getting older” (overall = 42%, Australia = 49%, and Vietnam = 35%). While the most frequently reported risk factor for the Vietnamese sample was “poor diet” (overall = 39%, Australia = 11%, and Vietnam = 64%). There were differences in the characteristics associated with the top causes of cancer identified by Australian and Vietnamese patients. Patients’ beliefs about what may have caused their cancer are complex and likely to be impacted by multiple factors, including the country from which they reside. Developing public awareness campaigns that are accurate and tailored to address the specific beliefs and possible misconceptions held by the target community are needed.