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Background We modified and evaluated an advance care planning (ACP) intervention, which had been shown to improve compliance with patient’s end of life (EoL) wishes, in a different patient population. Methods Patients with incurable cancer, and a Family Member (FM), were randomised one-to-one to usual care or usual care plus an ACP intervention, between April 2014 and January 2017. Oncologists and participants were non-blinded. ACP was based on the Respecting Patient Choices model, with an offer to provide individualised ranges for typical, best-case and worst-case scenarios for survival time. Seven facilitators (two oncology nurses, two nurses and three allied health professionals) delivered the intervention within 2 weeks of study enrolment. The primary outcome measure, assessed by interviewing the FM 3 months after patient death, was the FM perception that the patient’s wishes were discussed, and met. Results Six hundred and sixty-five patients from seven Australian metropolitan oncology centres were referred for consideration by their oncologists, 444 (67%) met the study inclusion criteria and were approached by a study researcher. Two hundred and eight patients (47%) and their FM entered the trial as dyads. Fifty-three (46%) dyads in the ACP group and 63 (54%) dyads in the usual-care group had complete primary outcome data (p = 0.16). Seventy-nine patients and 53 FMs attended an ACP discussion. Mean length of discussion was 57 min. FMs from 23 (43%) dyads allocated to ACP and 21 (33%) dyads allocated usual care reported the patient’s EoL wishes were discussed and met (difference 10%, 95% CI: −2 to 8, p = 0.27). There were no differences in EoL care received, patient satisfaction with care; FM satisfaction with care or with death; or FM well being. Rates of palliative care referral were high in both groups (97% vs 96%). Conclusions A formal ACP intervention did not increase the likelihood that EoL care was consistent with patients’ preferences.

Background: An increasing number and proportion of cancer patients with apparently localised disease are treated with chemotherapy and radiation therapy in contemporary oncology practice. In a pilot study of radiation-induced sarcoma (RIS) patients, we demonstrated that chemotherapy was associated with a reduced time to development of RIS. We now present a multi-centre collaborative study to validate this association. Methods: This was a retrospective cohort study of RIS cases across five large international sarcoma centres between 1 January 2000 to 31 December 2014. The primary endpoint was time to development of RIS. Results: We identified 419 patients with RIS. Chemotherapy for the first malignancy was associated with a shorter time to RIS development (HR 1.37; 95% CI: 1.08–1.72; P=0.009). In the multi-variable model, older age (HR 2.11; 95% CI 1.83–2.43; P

We developed a decision aid (DA) for patients with metastatic non-small cell lung cancer (NSCLC), to better inform patients of their prognosis and treatment options, and facilitate involvement in decision-making. In a pilot study, 20 patients with metastatic NSCLC attending outpatient clinics at a major cancer centre, who had already made a treatment decision, reviewed acceptability of the DA. The median age of the patients was 61 years (range 37–77 years), 35% were male, 20% had a university education, and most (75%) had English as a first language. Most had received chemotherapy, with 65% currently on treatment. Patients were not anxious at baseline and had clear understanding of the goals and toxicity of chemotherapy in advanced NSCLC. After reviewing the DA, patients' anxiety decreased slightly (P=0.04) and knowledge scores improved by 25% (P

Most cancer patients in westernised countries now want all information about their situation, good or bad, and many wish to be involved in decision-making. The attitudes to and use of shared decision-making (SDM) by cancer doctors is not well known. Australian cancer clinicians treating breast, colorectal, gynaecological, haematological, or urological cancer were surveyed to identify their usual approach to decision-making and their comfort with different decision-making styles when discussing treatment with patients. A response rate of 59% resulted in 624 complete surveys, which explored usual practice in discussing participation in decision-making, providing information, and perception of the role patients want to play. Univariate and multivariate analyses were performed to identify predictors of use of SDM. Most cancer doctors (62.4%) reported using SDM and being most comfortable with this approach. Differences were apparent between reported high comfort with SDM and less frequent usual practice. Multivariate analysis showed that specialisation in breast or urological cancers compared to other cancers (AOR 3.02), high caseload of new patients per month (AOR 2.81) and female gender (AOR 1.87) were each independently associated with increased likelihood of use of SDM. Barriers exist to the application of SDM by doctors according to clinical situation and clinician characteristics.

Optimal communication has been identified by patients and their families as one of the most important aspects of medical care at the end-of-life (Steinhauser et al, 2000; Curtis et al, 2001; Wenrich et al, 2001). Medical practitioners tend to underestimate the information needs of cancer patients (Degner et al, 1997a). The information needs of individual patients vary (Leydon et al, 2000; Jenkins et al, 2001). Hence, a blanket policy of fully informing and involving all patients may not best serve their interests. Communication may be improved when patients are able to ask questions that are of greatest concern to them. Some health professionals encourage patients to write down their questions and bring them to medical appointments, but patients may not know what questions to ask or how to articulate their concerns. Butow et al (1994) explored the use of a question prompt list (QPL) given to cancer patients before their initial consultation with oncologists. A QPL is a structured list of questions for the patient to ask the doctor if they wish. It is designed to encourage patient participation during a medical consultation and to assist patients in acquiring information that is suited to their needs and at their own pace. This simple and inexpensive intervention has been found to promote question asking about prognosis in three separate studies (Butow et al, 1994; Brown et al, 1999, 2001). In the most recent of these studies (Brown et al, 2001), provided the oncologist specifically addressed questions in the QPL during the consultation, those patients who received the prompt list were significantly less anxious immediately after the consultation and had better recall and significantly shorter consultations.

Patient participation in medical consultations has been demonstrated to benefit their subsequent psychological well being. Question asking is one way in which patients can be active. We investigated 2 means of promoting cancer patient question asking. One was the provision of a question prompt sheet to patients prior to their initial consultation with their oncologist. The second was the active endorsement and systematic review of the question prompt sheet by their oncologist. 318 patients with heterogeneous cancers, seeing one of 5 medical and 4 radiation oncologists for the first time, were randomised to either receive or not receive a question prompt sheet. Doctors were randomised to either proactively address or passively respond to the question prompt sheet in the subsequent consultation. Anxiety was assessed prior to the consultation. Consultations were audiotaped and content analysed. Anxiety was assessed again immediately following the consultation. Within the next 10 days patients completed questionnaires assessing information needs, anxiety and satisfaction and were given a structured telephone interview assessing information recall. Patients provided with a question prompt sheet asked more questions about prognosis compared with controls and oncologists gave significantly more prognostic information to these patients. Provision of the question prompt sheet prolonged consultations and increased patient anxiety; however, when oncologists specifically addressed the prompt sheet, anxiety levels were significantly reduced, consultation duration was decreased and recall was significantly improved. A patient question prompt sheet, used proactively by the doctor, is a powerful addition to the oncology consultation. © 2001 Cancer Research Campaign

Referral and reply letters are common means by which doctors exchange information pertinent to patient care. Twenty-eight semi-structured interviews were conducted exploring the views of oncologists, referring surgeons and general practitioners. Twenty-seven categories of information in referral letters and 32 in reply letters after a consultation were defined. The letters to and from six medical oncologists relating to 20 consecutive new patients were copied, and their content analysed. Oncologists, surgeons and general practitioners Australia wide were surveyed using questionnaires developed on data obtained above. Only four of 27 categories of referral information appear regularly (in > 50%) in referral letters. Oncologists want most to receive information regarding the patient's medical status, the involvement of other doctors, and any special considerations. Referring surgeons and family doctors identified delay in receiving the consultant's reply letter as of greatest concern, and insufficient detail as relatively common problems. Reply letters include more information regarding patient history/background than the recipients would like. Referring surgeons and family doctors want information regarding the proposed treatment, expected outcomes, and any psychosocial concerns, yet these items are often omitted. Consultants and referring doctors need to review, and modify their letter writing practices. © 1999 Cancer Research Campaign

Active participation in the medical consultation has been demonstrated to benefit aspects of patients' subsequent psychological well-being. We investigated two interventions promoting patient question-asking behaviour. The first was a question prompt sheet provided before the consultation, which was endorsed and worked through by the clinician. The second was a face to face coaching session exploring the benefits of, and barriers to, question-asking, followed by coaching in question-asking behaviour employing rehearsal techniques. Sixty patients with heterogeneous cancers, seeing two medical oncologists for the first time, were randomly assigned to one of three groups: two intervention groups and one control group. Sociodemographic variables and anxiety were assessed prior to the intervention which preceded the consultation. The consultations were audiotaped and subsequently analysed for question-asking behaviour. Anxiety was assessed again immediately following the consultation. Questionnaires to assess patient satisfaction, anxiety and psychological adjustment were sent by mail 2 weeks following the consultation. Presentation and discussion of the prompt sheet significantly increased the total number of questions asked and the number of questions asked regarding tests and treatment. Coaching did not add significantly to the effects of the prompt sheet. Psychological outcomes were not different among the groups. We conclude that a question prompt sheet addressed by the doctor is a simple, inexpensive and effective means of promoting patient question asking in the cancer consultation. © 1999 Cancer Research Campaign

A range of measures have been proposed to enhance the provision of information to cancer patients and randomized controlled trials have demonstrated their impact on patient satisfaction and recall. The current study explored the practice and views of oncologists, surgeons and general practitioners (GPs) with regards to providing patients with consultation audiotapes and summary letters. In stage 1, 28 semi-structured interviews with doctors were conducted to provide qualitative data on which to base a questionnaire. In stage 2, 113 medical oncologists, 43 radiation oncologists, 55 surgeons and 108 GPs completed questionnaires. Only one-third of doctors had ever provided patients with a copy of the letter written to the oncologist or referring doctor, and one-quarter had provided a summary letter or tape. The majority of doctors were opposed to such measures; however, a substantial minority were in favour of providing a letter or tape under certain conditions. More surgeons and GPs (> two-thirds) were opposed to specialists providing a consultation audiotape than oncologists (one-third). Gender, years of experience and attitude to patient involvement in decision-making were predictive of doctors' attitudes. The majority of doctors remain opposed to offering patients personalized information aids. However, practice and perspectives appear to be changing. © 1999 Cancer Research Campaign

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.

The characteristics of cell death were investigated after exposure of CCRF-CEM.f2 cells to five drugs over a broad concentration range; these were the glucocorticoid dexamethasone (DXM), the mitotic inhibitor vincristine (VIN) and three antimetabolites, methotrexate (MTX), 5'-fluoro-2'-deoxyuridine (FUdR) and 5'-fluorouracil (5-FU). Drug-treated cells were monitored for cell death mechanisms at different times by examining the pattern of DNA degradation, cell morphology and flow cytometric profile, together with effects on cell growth over 72 h. At growth-inhibitory drug concentrations, the first changes were cell cycle perturbations detectable after 4-6 h of drug exposure. The appearance of features characteristic of apoptotic cell death was noted after all drug treatments in the CCRF-CEM.f2 cell line, but the pattern and kinetics varied considerably. VIN induced apoptotic changes by 12 h, while DXM treatment caused apoptosis only after 48 h. Both MTX and FUdR induced morphological changes characteristic of apoptosis at least 24 h before internucleosomal DNA cleavage, which was detectable only after 48 h. In contrast, 5-FU did not cause internucleosomal DNA cleavage by 48 h at any concentration, despite the presence of morphologically apoptotic cells 24 h earlier. These data suggest that disruption of the cell cycle caused by drug treatment may be the common trigger initiating the drug-specific apoptotic sequence of dying cells. Images Figure 3 Figure 4

There are few data available on which to base recommendations for effective communication in the cancer consultation. This paper describes a computerised interaction analysis system designed specifically for the cancer consultation and its application in a study investigating the relationship between doctor-patient behaviour and patient outcomes. One hundred and forty-two cancer patients attending their first consultation with a cancer specialist were audio taped and a copy of the tape was retained for interaction analysis. Before the consultation patient anxiety and information and involvement preferences were measured. Outcomes included recall of information, patient satisfaction with the consultation and psychological adjustment to cancer. Doctor behaviour was shown to vary significantly according to the age, sex, involvement preferences and in/out-patient status of the patient. The ratio of doctor to patient talk was related to satisfaction with communication, while patients whose questions were answered showed better psychological adjustment at follow-up. The results suggest that patient-centred consultations lead to improved satisfaction and psychological adjustment. These data provide precise information about consultation behaviour which can be used in the documentation of current practice and the evaluation of new interventions to improve communication.

Exogenous purines (greater than or equal to 10(-5)M) can modulate the cytotoxicity of methotrexate (MTX) in cultured cells, protecting cells at low MTX concentrations (less than or equal to 8 x 10(-8) M) and markedly potentiating its effect at higher concentrations. The ability of hypoxanthine (HX) to modulate the effects of two antifolates-ICI 198583 (an inhibitor of thymidylate synthetase) and piritrexim (PTX, a lipophilic inhibitor of DHFR)-was investigated using cultured mouse leukaemic cells, L1210. HX (10(-4) M) was found to potentiate only the cytotoxicity of DHFR inhibitors (MTS and PTX), increasing cell kill by 20-70 fold to the level achieved by an equivalent concentration (10(-5) M) of ICI 198583 alone. Agarose gel electrophoresis of DNA extracted from cells exposed to antifolates for 24 h demonstrated that the chromatin was cleaved into multimers of 200 base pairs. This pattern of DNA cleavage indicates cell death via apoptosis. The degree of DNA fragmentation was found to be closely linked to cytotoxicity. DNA fragmentation increased from 50% in cells treated with 10(-5) M MTX or PTX to 70% when HX was added with the drugs, a level achieved by 10(-5)M ICI 198583 alone. HX potentiation of cytotoxicity was correlated with a substantial increase in dATP in conjunction with low dTTP pools. The specific potentiation of DHFR inhibitors by HX may be due to their inhibition of purine synthesis with a concurrent rise in PRPP levels. Addition of HX with MTX substantially raised intracellular purine levels via the salvage pathway as indicated by ribonucleotide pool measurements. ICI 198583, on the other hand, stimulated de novo purine synthesis with or without added HX. Treatment with MTX plus HX or ICI 198583 (with or without HX) caused a reduction of dTTP pools to 8% of untreated control and excess dATP accumulation. The subsequent elevation (to 300% of control) of the dATP pool may provide a signal for endonucleolytic fragmentation of DNA and subsequent cell death. Images Figure 3

This study provides an analysis of the structure of the initial cancer consultation, the consultation styles of medical and radiation oncologists, and their effect on patient outcomes. One hundred and fifty-five cancer patients attending their first consultation with either a medical or radiation oncologist were audiotaped and the transcripts were analysed using the Cancode computer interaction analysis system. Findings revealed that medical oncologists allowed patients and their families more input into the consultation and were rated as warmer and more patient-centred compared with radiation oncologists. However, radiation oncologists spent a longer period discussing, and were more likely to bring up, social support issues with patients. Both medical and radiation oncologists varied their consultation style according to the patient's gender, age, anxiety levels, prognosis, and education. Patients seeing an oncologist who was rated as warmer and discussed a greater number of psychosocial issues had better psychological adjustment and reduced anxiety after consultation. These findings provide current evidence that may be used to inform improvements of communication skills training for oncologists and highlight the need for future communication research to separately consider oncologists from different disciplines.

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 (

Adriamycin and cyclophosphamide are active agents in human and experimental tumours. Using the L1210 murine leukaemia, their effectiveness alone and in combination was studied. The combination is highly synergistic in this tumour, resulting in a greater than 50% survival rate when the agents used alone at optimal doses are not curative. DNA synthesis by tumour cells is substantially inhibited and the total ascitic population much reduced. In contrast, DNA synthesis in sensitive host tissues is less disturbed. There is no major difference in the pharmacology of the agents whether given alone or in combination. In very advanced disease the combination is no better than treatment with cyclophosphamide alone. The combination of adriamycin and melphalan in L1210 leukaemia also produces superior results to those obtained using either drug alone at its optimal dosage.

A lymphocyte clonal assay developed to quantitate in vivo somatic cell mutations at the hypoxanthine-guanine phosphoribosyltransferase locus was modified in order to study resistance to methotrexate. Even though nucleoside-free culture conditions were used methotrexate was not lethal to lymphocytes plated into micro-wells at greater than 10(2) cells/well. HPLC analysis of supernatants from wells plated initially with 10(4) cells/well in 100 microM methotrexate revealed the presence of micro-molar levels of hypoxanthine and thymidine by the 5th and 8th day of culture respectively. When lymphocytes were plated at less than or equal to 10(2) cells/well in nucleoside free medium, methotrexate was cytotoxic and micro-molar levels of thymidine together with hypoxanthine protected lymphocytes cultured under these conditions from toxicity. Modulation of nucleic acid antimetabolite cytotoxicity by nucleosides and bases has been recognised for some years. Nucleoside free culture conditions have been advocated for studying cellular sensitivity to antifolates to avoid such interfering factors. However our results indicate that metabolites from dying or damaged cells can prevent methotrexate cytotoxicity, further complicating the development of a suitable clonogenic assay for investigating antifolate sensitivity.

A rapid estimation of mutation frequency in tumours would be invaluable in cancer management. Considerable evidence suggests that drug resistance in tumours frequently arises as a consequence of spontaneous somatic mutation (Goldie & Coldman, 1979) and therefore the mutation rate of a tumour will be an index of the potential to develop drug resistance. Previous studies have compared the mutation rates of cell lines using cloning assays. Cifone & Fidler (1981) reported a higher mutation rate in metastatic variant of UV-2237 fibrosarcoma cells than in a clone of the same cell line with lower metastatic potential. Warren et al. (1981) reported that fibroblasts from patients with Bloom syndrome, which predisposes individuals to various cancers, had a 10-15 fold higher mutation rate than did fibroblasts from normal individuals. These findings have been important in correlating malignant capacity with genetic instability, but unfortunately, the techniques used have limited general application since few human tumour cells will form colonies on plastic. An alternative assay, soft agar cloning, has also been used for the determination of mutation rates in a variety of mammalian cell lines, including Chinese hamster ovary cells (Li & Shimizu, 1983) and the L5178Y mouse lymphoma cell line (Irr & Snee, 1982). Again, the low cloning efficiency of human tumour cells in soft agar (Hamburger et al., 1978) and the fact that this method selects only mutant cells which clone in agar limits the use of this assay to determine mutation frequency in human tumours. This latter source of error might bias the estimation of the mutation rate in favour of more malignant cells, which generally have higher cloning efficiencies (Elmore et al., 1983). Morley et al. (1983) and Albertini et al. (1982) have reported a limiting dilution technique for the measurement of mutation frequency in human lymphocytes. Culture conditions have been optimised for peripheral blood lymphocytes and a cloning efficiency of 20-60% has been obtained. Problems have been encountered, however, in studies of cultured lymphoblast lines with variable

Modulation of nucleic acid antimetabolite cytotoxicity by preformed purines and pyrimidines may not only complicate the interpretation of drug sensitivity tests and other in vitro studies but also adversely affect treatment in vivo. Previously we reported that in a lymphocyte clonal assay, thymidine and hypoxanthine released from dead or damaged cells reduced methotrexate cytotoxicity. We now report that the nucleoside transport inhibitor dipyridamole (DP), at 1.0 microM, abolished 3H-thymidine uptake into PHA stimulated lymphocytes, potentiated methotrexate cytotoxicity and reversed modulation of methotrexate cytotoxicity by exogenous thymidine and hypoxanthine. Normal growth of lymphocytes at high density was unaffected by 1.0-5.0 microM dipyridamole, while growth at low densities was only slightly reduced. Hydroxy-nitrobenzylthioguanosine (555) was a less potent inhibitor of 3H-thymidine uptake and was toxic to normal lymphocytes at concentrations inhibiting 3H-thymidine uptake. Nucleoside transport inhibitors isolate the cellular effects of nucleic acid antimetabolites, and provide a tool to study mechanisms of antifolate cytotoxicity.

The possible use of liposomes (phospholipid vesicles) to direct cytotoxic drugs to tumours has led us to investigate the tissue localization of i.v. injected 99m-Tc-labelled liposomes in cancer patients. Twenty mg or 300 mg doses of liposomal lipid (7:2:1 molar ratio of phosphatidylcholine : cholesterol : phosphatidic acid) were used in a study of 13 patients with advanced cancer and one with polycythaemia rubra vera (PRV). In all cases except the patient with PRV the major site of uptake of the label was the liver and spleen. In the patient with PRV the liver uptake was greatly reduced and the major site of uptake was found in regions corresponding to marrow. With the exception of one patient with a primary hepatoma, there was no significant tumour uptake of the label. Images Fig. 2 Fig. 3

Detailed flow cytometric analysis of cellular DNA content was performed on neoplastic tissue from 33 patients with malignant common epithelial ovarian tumours in order to investigate the intratumoral stability of ploidy and proliferative fraction. There was a remarkable stability, both spatial and temporal, in the DNA pattern for any particular tumour. Of 24 tumours that were analysed in multiple areas tumour ploidy was found to be a stable marker in all but 3 cases where regional variations were evident. In 9 patients serial analyses were performed on tumour obtained either at initial diagnosis (6 patients) or second look laparotomy (3 patients) and then some time later (7-17 months) at relapse or death and in all cases the tumour ploidy remained unchanged. In addition, 10 ovarian carcinomas established in nude mice have maintained a DNA content during serial passage similar to that of the original implanted tumour. In contrast in 50% of tumours that were evaluable for S-phase analysis we demonstrated a considerable intratumoral variability in the S-phase fraction. We conclude that cellular DNA content is a stable feature of ovarian carcinoma while S-phase fraction is commonly subject to intratumoral variation.

The emergence of drug resistance in tumours: a characteristic which may be exploited therapeutically

Human epithelial ovarian tumours were successfully established as xenografts in nude mice in 54% of cases. An evaluation of the biological characteristics of tumours propagated in nude mice was carried out and the functions investigated included morphology, growth kinetics, cellular DNA content, cell surface antigen expression and sensitivity to chemotherapy. To allow a more detailed study of the influence of ploidy on biological behaviour, xenografted tumour with varying degrees of aneuploidy and tumours with a common ancestry but different ploidies were also established. Although this is a highly selective model system favouring the growth of biologically aggressive tumours the xenografts, in general, reflect many of the characteristics of the tumours from which they were derived and are likely to provide a useful model for investigating the biology of ovarian cancer. Images Figure 1 Figure 2

Until recently the public water supply to Worksop contained high concentrations of nitrate. An epidemiological study has revealed that, compared with low nitrate control towns, Worksop has an increased death rate from gastric cancer. The possible role of the bacterial production of nitrosamines in the aetiology of these stomach cancer deaths is discussed.