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Biomedical subjects

M H Tattersall

Publications and source records attributed to M H Tattersall.

At least 55 records · Page 3Linked to original sources
PubMed1997

A randomized study of paclitaxel versus cyclophosphamide/methotrexate/5-fluorouracil/prednisone in previously untreated patients with advanced breast cancer: preliminary results. Taxol Investigational Trials Group, Australia/New Zealand.

When administered as a single agent to previously treated patients with advanced breast cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has good activity. This trial was undertaken to compare paclitaxel with standard chemotherapy as front-line treatment for this disease. Patients with measurable or evaluable metastatic breast cancer, no prior chemotherapy for metastatic disease, and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomized to receive either paclitaxel 200 mg/m2 intravenously over 3 hours for eight cycles over 24 weeks or standard treatment with oral cyclophosphamide 100 mg/m2/d days 1 to 14, intravenous methotrexate 40 mg/m2 days 1 and 8, intravenous 5-fluorouracil 600 mg/m2 days 1 and 8, and oral prednisone 40 mg/m2 daily days 1 to 14 (CMFP) for six cycles over 24 weeks. Patients whose disease progressed or relapsed were recommended for second-line therapy with epirubicin. Accrual has been completed with 209 patients randomized, and an interim analysis of the first 100 patients is reported here. Analysis of quality of life, assessed by the linear analogue scale and overall quality of life indices, is ongoing. Objective response occurred in 31% (confidence interval, 19% to 45%) with paclitaxel and 35% (confidence interval, 22% to 51%) with CMFP, with stable disease in an additional 33% and 29%, respectively. Median time to progression was 5.5 months with paclitaxel and 6.4 months with CMFP, with a median survival of 17.3 months for patients treated with paclitaxel and 11.3 months for those given CMFP. Grades 3 and 4 neutropenia occurred in 64% of patients with paclitaxel and 63% with CMFP. However, febrile neutropenia was the primary reason for hospitalization in 1% of paclitaxel courses, compared with 8% with CMFP. Major infections (World Health Organization grade 4) were seen in 7% of patients treated with CMFP, but in none of those given paclitaxel. Moderate or severe mucositis occurred in 13% of paclitaxel and 27% of CMFP patients. Alopecia and peripheral neuropathy were more common with paclitaxel. Quality of life assessments in the first 100 patients suggest better overall results for those treated with paclitaxel compared with CMFP. Preliminary analyses suggest that single-agent paclitaxel is well tolerated and provides control of metastatic cancer comparable to that of CMFP combination therapy when used as front-line therapy in an outpatient setting.

Antineoplastic Agents, Phytogenic↗
PubMed1996

When the diagnosis is cancer: patient communication experiences and preferences.

BACKGROUND: Discrepancies exist between reported experiences of patients when they have been given a diagnosis of cancer, published guidelines for telling a diagnosis, and patterns of communication patients rate as favorable. Several studies have identified what happened and what is important to cancer patients when told their diagnosis, but no studies have addressed subsequent communications concerning the implications of the diagnosis and treatment choices. This study extended previous research by investigating the experiences and preferences for communication about diagnosis, prognosis, and treatment of patients diagnosed with breast cancer or melanoma. METHODS: A self-report questionnaire was designed for this study based on previous research and qualitative data generated from focus groups. Patients with breast cancer or melanoma answered questions about their experiences with communication at the time of diagnosis and concerning prognosis, treatment and related issues. Comparisons were made between patient experiences, preferences and published guidelines. Differences between the experiences of breast cancer and melanoma patients were tested and the relationship between communication and subsequent psychological adjustment to cancer was assessed. RESULTS: Patient preferences for communication during diagnostic consultation were not always consistent with published guidelines. Type of cancer did not significantly affect patient preferences. Psychological adjustment was related to patient ratings of the quality of doctor discussion about treatment options, but not about the diagnosis of cancer and its implications. Patients who wanted more emotional support at the time of diagnosis subsequently experienced poorer psychological adjustment. CONCLUSIONS: The differences in patient preferences show that a list of prescriptions for how to disclose a cancer diagnosis is too simplistic. Guidelines for clinicians should be derived from patient-based data rather than be limited only to clinical opinion. Guidelines concerning communication at the time of diagnosis also need to address discussions concerning the implications of the diagnosis and making treatment decisions.

Adult↗
PubMed1996

Characteristics of cancer cell death after exposure to cytotoxic drugs in vitro.

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.

Antineoplastic Agents↗
PubMed1996

On the receiving end. V: Patient perceptions of the side effects of cancer chemotherapy in 1993.

BACKGROUND: A study conducted in 1983 to identify and rank the symptoms experienced by patients receiving cancer chemotherapy reported that vomiting and nausea were the most important symptoms experienced. With the advent of new antiemetic regimens and changes in cancer chemotherapy, it was anticipated that changes may have occurred in patient perception of symptoms. The study was therefore repeated in 1993. PATIENTS AND METHODS: One hundred and fifty-five cancer patients receiving chemotherapy at a large urban teaching hospital participated in the study. Patients selected from cards listing symptoms all those experienced and the five most troublesome. RESULTS: Patients reported experiencing an average of 20 symptoms (13 physical and 7 psychosocial). Nausea was reported as the most severe symptom followed by tiredness and loss of hair. Vomiting which was the most severe symptom in 1983, now ranked 5th. Differences were detected in the symptoms experienced and reported as most severe, between chemotherapy regimens, between older and younger patients and between males and females. CONCLUSIONS: The results suggest a reduction in the severity of some symptoms experienced while receiving chemotherapy and a shift from concerns about physical to psychosocial issues.

Adult↗
PubMed1996

The effect of adjuvant prednisone combined with CMF on patterns of relapse and occurrence of second malignancies in patients with breast cancer. International (Ludwig) Breast Cancer Study Group.

BACKGROUND: The addition of low-dose prednisone (p) to the adjuvant regimen of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) allowed patients to receive a larger dose of cytotoxics when compared with those on CMF alone. However, disease-free survival and overall survival were similar for the two groups. To test the hypothesis that low-dose prednisone might influence the efficacy of the cytotoxic regimen used, the toxicity profiles of the two treatment regimens and the patterns of treatment failure (relapse, second malignancy, or death) were examined. PATIENTS AND METHODS: 491 premenopausal and perimenopausal patients with one to three positive axillary lymph nodes included in International (Ludwig) Breast Cancer Study Group (IBCSG) trial I from 1978 to 1981 and randomized to receive CMF or CMFp were analyzed for differences in long-term outcome and toxic events. The 250 patients assigned to CMF and prednisone received on the average 12% more cytotoxic drugs than those who received CMF alone. RESULTS: The 13-year DFS for the CMFp group was 49% as compared to 52% for CMF alone, and the respective OS percents were 59% and 65%. Several toxic effects such as leukopenia, alopecia, mucositis and induced amenorrhea were reported at a similar incidence in the two treatment groups. Using cumulative incidence methodology for competing risks, we detected a statistically significant increase in first relapse in the skeleton for the CMFp group at 13 years follow-up with a relative risk (RR) of 2.06 [95% confidence interval (CI), 1.23 to 3.46; P = 0.004]. Patients with larger tumors in the CMFp regimen were especially subject to this increase with a RR for failure in the skeleton of 3.32 (95% CI, 1.57 to 7.02; P = 0.0005). CMFp-treated patients also had a larger proportion of second malignancies (not breast cancer), with RR of 3.34 (95% CI, 0.91 to 12.31; P = 0.09). CONCLUSIONS: Low-dose continuous prednisone added to adjuvant CMF chemotherapy enabled the use of higher doses of cytotoxics. This increased dose had no beneficial effect on treatment outcome, but was associated with an increased risk for bone relapses and a small, not statistically significant increased incidence of second malignancies. The effects of steroids, which are widely used as antiemetics (oral or pulse injection) together with cytotoxics, should be investigated to identify their influence upon treatment outcome.

Antineoplastic Agents, Hormonal↗
PubMed1996

Concomitant and neoadjuvant chemotherapy in conjunction with radiotherapy in the management of locally advanced cervical cancer.

Radiotherapy is standard treatment for women with locally advanced cervical cancer (stage IIB-IVA). Radiotherapy fails to control disease progression within the irradiated field in more than 40% of patients. The disease bulk is a major factor limiting the curative probability of pelvic radiotherapy. Chemotherapy has been integrated with pelvic radiotherapy with the goal of improving local tumor control and treating microscopic metastases outside the radiotherapy field. Simultaneous chemotherapy and radiotherapy, neoadjuvant chemotherapy followed by radiotherapy, and adjuvant chemotherapy after radiotherapy, have been investigated. Hydroxyurea during pelvic radiotherapy has been reported to be associated with an improved progression-free (P = .05) and survival (P = .066) advantage. Several randomized trials of concomitant radiotherapy with fluorouracil, mitomycin, or cisplatin have been completed, but no results are published. Neoadjuvant chemotherapy with cisplatin-containing regimens followed by radiotherapy has been studied in several randomized trials. Although tumor response after chemotherapy is reported in more than 50% of patients, no improvement in local disease control or in survival has been noted overall. In one large trial, neoadjuvant chemotherapy was inferior to standard pelvic radiotherapy in terms of local control and survival. Adjuvant chemotherapy after radiotherapy has been little studied, and no randomized trials have been reported. The results of trials in progress or completed but not yet reported will determine further clinical research directions. Chemotherapy during and after pelvic radiation therapy has been little studied.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

5,10-Dideazatetrahydrofolic acid reduces toxicity and deoxyadenosine triphosphate pool, expansion in cultured L1210 cells treated with inhibitors of thymidylate synthase.

5,10-Dideazatetrahydrofolic acid (DDATHF) reduces de nova purine biosynthesis by inhibiting glycinamide ribonucleotide transformylase. ICI D1964 and CB3717 are folate-based inhibitors of thymidylate synthase (TS). Fluorodeoxyuridine (FdUrd) following metabolism to FdUMP also inhibits TS. In cultured L1210 cells DDATHF reduced the toxicity of ICI D1694, CB3717 and FdUrd in a concentration-dependent manner. This protection correlated with a prevention of the increase in intracellular dATP pools seen in cells exposed to the TS inhibitors alone. The possibility that DDATHF protection might be due to competition for cell entry is not likely since CB3717 and FdURD but not ICI D1694 enter the cell by independent transport processes. Exogenous hypoxanthine (HX) had no effect on the toxicity of TS inhibitors. However, HX increased the protective effect of DDATHF from ICI D1694 toxicity, had no effect on the CB3717-DDATHF interaction, and reduced the protective effect of DDATHF on FdUrd toxicity. HX prevented the fall in dATP levels caused by DDATHF addition to cells treated with TS inhibitors. HX had different effects on dTTP levels in cells treated with DDATHF and quinazoline TS inhibitors compared to FdUrd. Together these results support the hypothesis that imbalance in dTTP and dATP pools is an important determinant of cytotoxicity in antifolate-treated cells. In addition, these findings suggests that intracellular reduced folates interconvert to catalyse reactions in metabolically perturbed cells.

Animals↗
PubMed1995

Activation and cytotoxicity of 2-alpha-aminoacyl prodrugs of methotrexate.

In an effort to improve the selectivity of the anticancer drug methotrexate (MTX), a series of potential prodrugs in which the 2-amino group was acylated with various alpha-amino acids (as well as L-pyroglutamic acid) was synthesized. Such derivatives are anticipated to be hydrolysed to MTX by appropriate aminopeptidases localized (over-expressed naturally or targeted as anti-tumor antibody conjugates) in the vicinity of the tumor. The L-leucyl, L-valyl, L-isoleucyl, D-alanyl and L-pyroglutamyl derivatives were assessed as to their suitability as prodrugs. Except for the L-pyroglutamyl compound, all derivatives decomposed slowly when incubated in phosphate buffer, pH 7.3; the formation of MTX was minimal. No major differences were observed when serum was included in the incubation medium, except for the L-leucyl compound, which was hydrolysed to MTX. The L-leucyl, L-valyl and L-isoleucyl derivatives were hydrolysed readily to MTX by aminopeptidase M (EC 3.4.11.2), while the L-pyroglutamyl and D-alanyl compounds were activated by pyroglutamate aminopeptidase (EC 3.4.19.3) (from Bacillus amyloliquefaciens) and D-aminopeptidase (from Ochrobactrum anthropi), respectively. When tested for inhibition of the target enzyme dihydrofolate reductase (DHFR; EC 1.5.1.3), 2-L-valyl-MTX showed inhibition two orders of magnitude poorer than that given by MTX, in agreement with the expectation that acylation of the 2-amino group reduces binding to DHFR. After treatment of this derivative with aminopeptidase M, the extent of inhibition correlated with the amount of MTX formed. MTX derivatives alone or in combination with the complementary peptidase were tested for cytotoxicity on murine L1210 cells in culture. The above-listed derivatives were considerably less cytotoxic than MTX, except for the L-leucyl derivative which showed considerable cytotoxicity. When the appropriate exogenous peptidase was included, the cytotoxicity of the activated prodrugs approached that of MTX. These results indicate that 2-L-leucyl-MTX is unsuitable as a prodrug since it is activated prematurely by serum enzymes. Although the L-valyl and L-isoleucyl derivatives do not hydrolyse to MTX in serum and are readily activated, they are not ideal prodrugs since they decompose under physiological conditions; the properties of the decomposition product will have a bearing on the ultimate suitability of these compounds. 2-L-Pyroglutamyl-MTX is the best candidate prodrug, showing stability and ready activation by the appropriate aminopeptidase.

Aminopeptidases↗
PubMed1995

Identification of E6/E7 transcription patterns in HPV 16-positive cervical cancers using the reverse transcription/polymerase chain reaction.

Studies indicate the presence of four different forms of human papillomavirus (HPV) E6/E7 mRNA resulting from differences in transcription patterns and post-transcriptional nuclear splicing. Through a retrospective analysis of 28 cervical cancer patients, correlations were sought between E6/E7 transcription patterns and histologic type, FIGO stage, and tumor aggression. A combined reverse transcription/polymerase chain reaction was used to study E6/E7 transcription patterns in fresh and/or fixed paraffin-embedded tissues of HPV 16-positive cervical cancers. Random cervical biopsies from nine women with no history of cervical disease were included as controls. Two sets of primers used in the investigations detected the full-length (FL) E6, E6*I, and E6*II mRNAs and the FL E6 and E6*I mRNAs, respectively; eight of the tumors were also analyzed using a third primer combination designed to identify the E6*III mRNA. At least two of the transcripts were detected in all of the tumors, whereas E6/E7 mRNAs were not identified in any of the control cervical biopsies. Overall, the transcription patterns were consistent, but the major E6*I mRNA was not detected in two of the tumors. No relationship was found between the E6/E7 transcription patterns and the histological type and differentiation of the tumors, nor with the FIGO stage and the clinical behavior of the disease. The study confirms that E6/E7 transcription is a constant feature of HPV 16-related carcinoma, but the findings indicate that there may be no clinical advantage in adding E6/E7 mRNA detection to the routine assessment of cervical tumors.

Adult↗
PubMed1995

Human papillomavirus deoxyribonucleic acid as a prognostic indicator in early-stage cervical cancer: a possible role for type 18.

OBJECTIVE: Our purpose was to determine the prognostic significance of human papillomavirus deoxyribonucleic acid in cervical cancers. STUDY DESIGN: The polymerase chain reaction was used to detect human papillomavirus deoxyribonucleic acid types 6, 11, 16, 18, 31, 33, 52, or 58 in tumors from 148 patients (equal numbers of whom were disease free or had relapses) surgically treated for stage IB or IIA cancers in a major Australian hospital. Cox regression modeling was used to assess the effect of human papillomavirus status on tumor recurrence, taking into account patient age, clinical stage, histologic node status, and type of tumor. RESULTS: Seventy of 74 (95%) of the recurring tumors and 62 of 74 (84%) of the nonrecurring tumors were human papillomavirus deoxyribonucleic acid positive. The rates of positivity of types 16 and 18 were 64% versus 31% in the recurrers and 65% versus 14% in the nonrecurrers. Human papillomavirus type 18 positivity was associated with a greater risk of recurrence than was type 16 positivity (hazard ratio 1.8; p = 0.03). Clinical stage, nodal metastasis, and young age (< or = 35 years) also had adverse effects on relapse (hazard ratio for each approximately 2). CONCLUSION: Human papillomavirus type 18 positivity is a risk factor for tumor recurrence in surgically treated cervical cancer.

Adult↗
PubMed1995

Computer-based interaction analysis of the cancer consultation.

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.

Adolescent↗
PubMed1995

Phase II study of high dose epirubicin in combination with cyclophosphamide in patients with advanced breast cancer.

BACKGROUND: Combination chemotherapy for metastatic breast cancer will palliate symptoms in the majority of patients but only a small percentage will have prolonged survival. Higher doses of doxorubicin lead to increased response rates in breast cancer and early studies have shown that epirubicin could be tolerated in higher doses with less relative toxicity than doxorubicin. AIMS: This study was initiated to assess the dose of epirubicin that could be tolerated by escalating its dose while maintaining a fixed dose of cyclophosphamide. Simultaneously tumour response rate, spectrum of toxicities, duration of response and overall survival in patients with metastatic breast cancer were assessed. METHODS: Patients with metastatic breast cancer commenced chemotherapy with a starting dose of epirubicin of 120 milligram per metre squared (mg/m2) and cyclophosphamide 600 mg/m2. The dose of epirubicin was to be escalated or reduced depending on toxicity. RESULTS: Forty female patients were entered into this study and three patients withdrew because of toxicity. Overall tumour response rate was 75% with 27.5% of patients obtaining a complete response. Median time to progressive disease was 35 weeks and median overall survival was 48 weeks, with median survival for complete responders being 103 weeks. Thirty-one (77%) patients completed five or more courses of treatment. Haematological toxicity was the main side effect and 70% of patients required a dose reduction. No patients were eligible for a dose escalation. One patient died as a consequence of neutropenic sepsis. Four (10%) patients had treatment ceased because of decrease in left ventricular ejection fraction and one patient died as a consequence of heart failure. Four patients remain alive. CONCLUSIONS: High dose epirubicin combined with cyclophosphamide is an effective treatment regimen for metastatic breast cancer obtaining higher overall response rates with increased percentage complete responses compared to conventional dose chemotherapy. Although toxicity was increased, high dose chemotherapy was well tolerated and mortality associated with treatment was not increased. No dose escalations of epirubicin were possible and a dose of 90 mg/m2 of epirubicin would be the maximum dose when used in combination with cyclophosphamide. Further trials are required to determine the influence of this high dose therapy on survival duration and whether comparable benefits can be achieved with shorter durations of therapy.

Adenocarcinoma↗
PubMed1995

Writing to referring doctors after a new patient consultation. What is wanted and what was contained in letters from one medical oncologist?

BACKGROUND: There are no Australasian data on the preferred information content of letters from consultant physicians to referring doctors. AIMS: To survey referring general practitioners (GPs) and specialists concerning their preferences for letters from a consultant physician after a new patient consultation to include different categories of information. To investigate the information content of letters written by one medical oncologist to referring doctors after a new patient consultation and contrast with that of individualised letters written to patients. METHODS: Fifty-five referring GPs and 53 specialists were sent a questionnaire seeking their views on the information content of letters from consultant physicians. Ninety-four letters after a new patient consultation were selected at random and analysed for their information content, and compared with 182 individualised letters sent to patients. RESULTS: Referring doctors wanted letters to contain details of diagnosis, clinical findings, test results and recommended future tests, treatment options, side effects and prognosis. Letters to referring doctors contained 19 items of information (range 8-33), while letters to patients contained a mean of 5.6 'salient' points (range 5-7). Both letters almost always stated the diagnosis, the presenting history and recommended treatment. Letters to patients more commonly presented information about prognosis, further tests, and explanation of symptoms than letters to doctors. In contrast, letters to referring doctors contained more information concerning the past medical, family, and drug history, clinical findings and test results. CONCLUSIONS: Letters sent by a consultant oncologist are not well tailored to the information needs of the referring clinician. Summary letters sent to patients may be modified to include information required by referring doctors.

Cross-Over Studies↗
PubMed1995

Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer. Cervical Cancer Study Group of the Asian Oceanian Clinical Oncology Association.

PURPOSE: Pelvic radiation is standard treatment for women with stage IIb to IVa cervical cancer, but treatment results are disappointing, particularly for women with bulky tumors. We investigated the role of primary chemotherapy followed by pelvic radiotherapy in a randomized trial. PATIENTS AND METHODS: Two hundred sixty patients with stage IIb and IVa cervical cancer received either standard pelvic radiotherapy or primary chemotherapy with cisplatin 60 mg/m2 and epirubicin 110 mg/m2 administered at 3-week intervals for three cycles, followed by pelvic radiotherapy. RESULTS: Ninety-nine patients have relapsed with a median follow-up duration of 1.3 years; in 62 patients, the first site of progressive disease was the pelvis. Patients who received primary chemotherapy had a significantly higher pelvic failure rate than those who received radiotherapy alone (P < .003). Seventy-six patients have died, and those who received primary chemotherapy had significantly inferior survival compared with those who received radiotherapy alone (P = .02). Tumor response following chemotherapy was observed in 63%. After radiotherapy, tumor response occurred in 72% of those who received combined modality treatment, compared with 92% of those who received radiotherapy alone. CONCLUSION: Primary chemotherapy with epirubicin and cisplatin, although resulting in tumor response in a significant proportion of patients, is accompanied by an inferior local control rate and survival compared with standard pelvic radiotherapy alone.

Adenocarcinoma↗