Thermal neutron capture therapy: the Japanese-Australian clinical trial for malignant melanoma.
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Australia↗
Biomedical subjects
A S Coates
Publications and source records attributed to A S Coates.
Costs and benefits of adjuvant therapy in breast cancer: a quality-adjusted survival analysis.
The use of adjuvant chemotherapy for postmenopausal patients with early breast cancer remains controversial because the potential benefits in terms of prolongation of disease-free survival (DFS) and overall survival (OS) must be balanced against the toxicity of treatment. Following mastectomy, 463 evaluable postmenopausal women with node-positive breast cancer were randomized to receive either chemoendocrine therapy for 1 year, or endocrine therapy alone for 1 year, or no adjuvant therapy (Ludwig Trial III). At 7-years median follow-up, OS was longer for the chemoendocrine-treated patients compared with controls (P = .04) and compared with the adjuvant endocrine therapy-alone group (P = .08). In order to balance this therapeutic advantage against the toxic effects of treatment, OS time was divided into time with toxicity (TOX), time without symptoms and toxicity (TWiST), and time after systemic relapse (REL). TOX and REL were weighted by coefficients of utility relative to TWiST and the results added to give a period of quality-adjusted survival (Q-TWiST). Benefits measured by Q-TWiST generally favored chemoendocrine therapy. For example, if TOX and REL were both given utility coefficients of 0.5 relative to 1.0 for TWiST, then by 7 years the average Q-TWiST for chemoendocrine therapy was 6.7 months longer than for no-adjuvant therapy (P = .05) and 4.1 months longer than for endocrine therapy alone (P = .20). Quality-adjusted survival analysis is recommended in assessing costs and benefits of toxic adjuvant therapy. In this example, it supports the use of chemoendocrine therapy in postmenopausal node-positive patients for a wide range of relative values assigned to periods with symptoms and toxicity.
Antineoplastic Agents↗
Chemotherapy of advanced head and neck cancer: updated results of a randomized trial of the order of administration of sequential methotrexate and 5-fluorouracil.
One hundred and twenty-seven patients with advanced or recurrent squamous cell carcinoma of the head and neck (HNC) were randomized to treatment with methotrexate (MTX) followed 1 hour later by 5-fluorouracil (5-FU) (sequence MF), or 5-fluorouracil followed after 1 hour by methotrexate (sequence FM). One hundred and seventeen patients were evaluable for response. There was no significant difference in response rates between the MF and FM sequences. Overall, 8 patients (6.8%) achieved complete response (CR) and 46 (39.3%) partial response (PR). In 95 previously untreated patients, the overall response rate (CR + PR) was 50%, compared with 31% for previously treated patients (P = 0.02). Survival duration significantly favored the FM sequence in univariate analyses (P = 0.04). Stepwise multivariate Cox model analysis showed that poor performance status (Eastern Cooperative Oncology Group) at study entry (P less than 0.001) and prior radiotherapy (P = 0.03) were significant adverse predictors for survival. When allowance was made for these factors, a survival difference in favor of the FM sequence remained (P = 0.003). Sequential MTX followed 1 hour later by 5-FU is not recommended for treatment of HNC.
Antineoplastic Combined Chemotherapy Protocols↗
Patient treatment preference in advanced breast cancer: a randomized cross-over study of doxorubicin and mitozantrone.
Twenty-two patients with advanced breast cancer participated in a randomized cross-over study of one cycle each of doxorubicin followed 3 weeks later by mitozantrone or vice versa. Before further treatment, patients selected which drug they wished to continue. Of 18 patients completing the study, 13 chose to continue mitozantrone, 2 doxorubicin and 3 had no preference (P = 0.007). Patients were told to assume similar efficacy of the two drugs and drug preference was based primarily on side-effects. Patient self-assessment of quality of life and physician assigned toxicity scores both indicated that nausea and vomiting, appetite and alopecia were significantly worse following doxorubicin than after mitozantrone. Except for alopecia, no significant period or carry-over effects were noted although the power of the study to detect such interactions was low. This study design may prove useful in enabling patients to select their preference between two treatments of similar efficacy.
Adult↗
Drug resistance in clinical practice: patterns of treatment failure in patients receiving systemic therapy for advanced breast cancer.
Strategies for overcoming the causes of drug resistance should take account of the patterns of treatment failure seen in clinical practice. We have analysed the patterns of disease progression in 267 patients with advanced breast cancer receiving systemic therapy. First disease progression on therapy most commonly occurred in tissues involved by tumour at the commencement of treatment. However in 40% of patients, first documentation of disease progression included a tissue not previously known to contain metastatic disease. In only 3% of patients was this new tissue the central nervous system. This pattern of disease progression was not influenced by treatment type (i.e. endocrine or cytotoxic), tumour response to treatment, oestrogen receptor status, prior adjuvant cytotoxic treatment, or disease free interval. These results question the wisdom of always ceasing existing therapy and substituting new treatment when progressive disease is first documented.
Antineoplastic Agents↗
Metastatic adenocarcinoma of unknown primary site. A randomized study of two combination chemotherapy regimens.
Of 101 patients with symptomatic adenocarcinoma or undifferentiated carcinoma of unknown primary site, 95 were evaluable for the effects of two randomized chemotherapy regimens. Forty-eight patients received combination doxorubicin and mitomycin C (DM) and 47 received combination cisplatin, vinblastine and bleomycin (PB). Response rates were not significantly different between the two treatment groups, 42% for DM and 32% for PVB, with an overall response rate of 37.1%. Survival differences for DM and PVB treated groups were not significantly different, with 18 weeks and 25 weeks median survivals respectively. Toxicities were unequal for the two treatment groups with increased haematological toxicity for DM and greater gastrointestinal toxicity for PVB. The authors conclude both therapies were of limited efficacy in the treatment of ACUP patients and emphasize that only symptomatic patients should be considered for such therapies.
Adenocarcinoma↗
Chemotherapy of adult soft tissue sarcoma with combination of doxorubicin and methotrexate.
Thirty-six adult patients with measurable advanced soft tissue sarcoma were treated with a combination of doxorubicin (70 mg/m2) and methotrexate (50 mg/m2) iv every 21 days. Partial remission was seen in ten of 33 evaluable patients (30%). Median duration of remission was 23 weeks, and median survival was 42 weeks. Bone marrow toxicity was the main toxic effect; 23% of the patients had a nadir leukocyte count less than 2.0 X 10(9)/L during therapy. These results do not suggest any therapeutic advantage in adding methotrexate to doxorubicin in this context.
Adult↗
Randomised comparison of procedures for obtaining informed consent in clinical trials of treatment for cancer.
Methods of obtaining informed consent have evolved differently in Western countries without substantive information on the impact of these different practices on the patients. A randomised study was performed to compare two commonly adopted methods of seeking consent to randomised treatment: an individual approach at the discretion of each doctor and a uniform policy of total disclosure of all relevant information. The impact of both consent procedures on the patient's understanding and anxiety levels and on the doctor-patient relationship was assessed by means of a questionnaire given soon after the consent interview. Fifty seven patients were assigned at random to two groups: to 29 patients an individual approach to seeking consent was adopted and to 28 patients all relevant information was given. Seven patients refused consent to randomised treatment, with slightly more refusals by patients in the total disclosure group (5 v 2, p = 0.25). The main effects of total disclosure of all information compared with an individual approach to seeking consent were: a better understanding of treatment and side effects and of research aspects of the treatments; less willingness to agree to randomised treatment; and increased anxiety. No significant differences were found in patients' perceptions of the doctor-patient relationship. A repeat questionnaire given three to four weeks later no longer showed significant differences between the two groups.
Anxiety↗
Chemotherapy in metastatic melanoma: phase II studies of amsacrine, mitoxantrone and bisantrene.
In a phase II study 20 patients with measurable metastatic melanoma were treated with amsacrine 120 mg/m2 every 3 weeks. No objective responses were observed. In a separate study 29 patients received mitoxantrone 12-14 mg/m2 every 3-4 weeks. One objective partial response was seen. The drug was well tolerated. Seventeen patients were treated with bisantrene 135-200 mg/m2 weekly. No objective responses were observed. Phlebitis was the major non-hematologic toxicity of bisantrene. These agents are not recommended for treatment of malignant melanoma.
Aminoacridines↗
Effects of recombinant leukocyte interferon (rIFN-alpha A) on tumour growth and immune responses in patients with metastatic melanoma.
Studies were initiated to assess the response of patients with disseminated melanoma to recombinant alpha interferon (rIFN-alpha A) and to monitor effects of rIFN-alpha A on several tests of immune function. Twenty patients were treated with rIFN-alpha A given by i.m. injection in escalating doses from 15 to 50 X 10(6) um-2. The responses of two patients were considered unevaluable. Of the remainder there was complete remission of tumour in two and stable disease in two. Subsequent progression of tumour in one of the latter patients coincided with development of antibodies to IFN. Side effects (usually fatigue) were dose rate limiting in 11 patients. Laboratory tests on samples taken 6 hours after rIFN-alpha A indicated a marked lymphopenia and a reduction in natural killer (NK) cell activity particularly against K562 target cells. Longer term changes measured in samples taken 2 days after the previous rIFN-alpha A injections consisted of neutropenia and an increase in the T4/T8 ratio due mainly to a relative increase in OKT4 positive T cells compared to OKT8 positive T cells. NK activity against the K562 target cell increased in most patients during the first week of treatment and then returned to below or near pretreatment levels thereafter against the K562 target cell. This contrasted with NK activity against the melanoma target cell which showed a more gradual increase over the duration of the treatment in 6 patients. The latter correlated with an increase in mitogen stimulated IL 2 production from their blood lymphocytes and may indicate that the cytotoxic activity resulted from lymphokine-activated killer (LAK) cells. These results confirm the activity of rIFN-alpha A against melanoma in certain patients. They suggest that further studies are needed to select patients who may respond to rIFN-alpha A and to optimize treatment regimens. Tests of IL 2 production and LAK activity may assisted in achieving these objectives.
Adult↗
Cisplatin, vinblastine, and bleomycin in inoperable non-small cell lung cancer.
Forty two patients with inoperable non-small cell lung cancer were entered into a phase II study of the combination chemotherapy regimen PVB (cisplatin 60 mg/m2 by intravenous infusion over two hours on day 1, vinblastine 4 mg/m2 by intravenous bolus on days 1 and 2, and bleomycin 15 mg intramuscularly on days 1, 8, and 15), repeated at three weekly intervals. Twelve of 40 evaluable patients (30%) achieved partial responses; there were no complete responses. The median duration of response was 16 weeks (range greater than 8-73 weeks). The median survival of responding patients calculated from entry to the study until death (40 weeks) was superior to that of patients failing to respond (15 weeks). Treatment was accompanied by signs of moderate toxicity, particularly myelosuppression, nausea and vomiting, alopecia, and neuropathy. One patient died from a neutropenic infection. PVB is a moderately toxic regimen for non-small cell lung cancer and appears similar in efficacy and toxicity to high dose cisplatin and vindesine.
Adenocarcinoma↗
Randomized trial of combination chemotherapy in hormone-resistant metastatic prostate carcinoma.
A prospective randomized study was conducted in 51 patients with stage D hormone-resistant prostatic carcinoma, comparing a combination of doxorubicin and lomustine (DC) with cyclophosphamide and 5-FU (CF). Patients were assessed objectively (employing National Prostate Cancer Project criteria) and subjectively (using a numerical scoring scheme). Each regimen was well tolerated with acceptable levels of myelosuppression. The objective partial response rate was 57% for DC and 8% for CF. Objective stabilization occurred, respectively, in 14% and 44% of the patients. Similarly, DC demonstrated a significantly superior subjective response rate (partial plus complete) of 82%, compared to 48% for CF. Patients with poor initial performance status or liver involvement had significantly lower response rates and reduced survival. Overall, there was no significant difference in survival between the two arms, reflecting the similarity between DC and CF in total objective response rate (partial response plus stable disease). DC provided superior palliation and was well tolerated by an essentially geriatric population.
Aged↗
Treatment of advanced squamous-cell carcinoma of the head and neck with a combination of cisplatin, vinblastine, and bleomycin.
Fifty patients with advanced, measurable, squamous-cell cancers of the head and neck received treatment with a combination of cisplatin, vinblastine, and bleomycin (PVB). The tumours in 25 patients (50%) responded to treatment (partially in 17 and completely in eight). The median duration of response was 18 weeks, and that of survival was 31 weeks. Toxicity was moderately severe; myelotoxicity occurred in 13 patients, and nausea and vomiting in 22 patients.
Adolescent↗
Combination therapy with methotrexate and 5-fluorouracil: a prospective randomized clinical trial of order of administration.
Because of biochemical and tissue culture evidence casting doubt on the physiologic relevance of reported synergy afforded by sequential administration of methotrexate (MTX) followed by 5-fluorouracil (5-FU), a randomized controlled clinical trial was conducted in 108 patients with advanced cancer, including 70 with squamous cell carcinoma (SCC) of the head and neck, nine with SCC of other primary sites, 24 with colorectal, and five with gastric adenocarcinomas. Patients were randomized to receive weekly therapy consisting of MTX followed one hour later by 5-FU, or 5-FU followed one hour later by MTX. There was a trend to higher tumor response rates in patients treated with MTX before 5-FU (45% v 33% overall; 65% v 39% in patients with previously untreated head and neck cancer), but these differences were not significant, either by chi-square test or by multivariate stepwise logistic regression. The trend in survival favoring the reverse sequence of 5-FU before MTX was not significant in univariate analyses. Stepwise multivariate Cox model analysis showed that Eastern Cooperative Oncology Group performance status at study entry was the major prognostic factor for survival (P less than 0.001), but among the 70 patients with head and neck cancer, the sequence of drug administration was the only other significant prognostic factor for survival, and favored the sequence of 5-FU followed by MTX (P less than 0.025).
Adenocarcinoma↗
Influence of cellular DNA content on survival in advanced ovarian cancer.
Tumor cellular DNA content was measured by flow cytometry in 91 patients with advanced ovarian cancer, using a new and simple technique which allows archival paraffin-embedded tissue to be studied; 69% of the tumors were aneuploid, and 31% were diploid. Tumor ploidy was shown by multivariate Cox model analysis to be an independent prognostic variable and the major determinant of survival. Patients with diploid tumors survived significantly longer than did those with aneuploid tumors (p much less than 0.0001; X2 = 25.44; d.f. = 1).
DNA, Neoplasm↗
Surgery in patients with advanced germ cell malignancy following a clinical partial response to chemotherapy.
Twenty-one patients with metastatic germ cell tumors achieved only partial clinical tumor regression following chemotherapy, and underwent surgical biopsy or resection of the residual tumor deposits. Sixteen (76%) are at present clinically disease-free after a median 30 + months (range 17-50 months) from the time of surgery, and five (24%) died after 9-29 months. Adverse prognostic signs were the finding of persistent cancer at histopathological examination of the resected tumor masses, and the presence of elevated serum tumor markers at the time of surgery. Postchemotherapy surgery in this setting provides tissue for the prognostically important histopathological examination on which a decision regarding further chemotherapy may be based. In addition, it provides tumor bulk reduction in the cases of differentiated teratoma and persistent cancer.
Adolescent↗
Influence of non-specific immunologic factors on prognosis in advanced bronchogenic carcinoma.
Fifty-nine evaluable patients with stage III bronchogenic carcinoma, participating in a randomized clinical trial evaluating the effect of adjuvant immunotherapy with levamisole or BCG in the treatment of clinically advanced lung cancer, were studied for their immunocompetence by in vitro and in vivo assays. Immunological tests consisted of measurements of natural killer (NK) cell and killer (K) cell cytotoxicity, skin testing reactivity to recall antigens, absolute lymphocyte count, and serum immunoglobulin (Ig) levels. Pretherapy K cell cytotoxic levels, skin test reactivity to trichophyton antigen, and increased IgA levels were predictive of the overall clinical course. Despite non-specific immunotherapy, progressive decline of NK and K cell cytotoxicity occurred during the course of the disease. These findings, however, were of limited clinical value. Initial performance status and disease extent significantly influenced time to progression and survival. Little further prognostic information was obtained from the immunological tests over those provided by clinical performance status and disease extent. No statistically significant differences were found in either time to progression or survival between controls and patients receiving either levamisole or BCG.
Carcinoma, Bronchogenic↗
Leucocytoclastic vasculitis and skin necrosis following subcutaneous heparin calcium.
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Aged↗