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Biomedical subjects

I F Tannock

Publications and source records attributed to I F Tannock.

At least 37 records · Page 2Linked to original sources
PubMed2001

A retrospective analysis of the relationship between changes in serum PSA, palliative response and survival following systemic treatment in a Canadian randomized trial for symptomatic hormone-refractory prostate cancer.

BACKGROUND: To investigate the relationship between changes in serum PSA, palliative response and survival following systemic treatment for symptomatic hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: A retrospective review of 161 patients, treated with mitoxantrone and prednisone (M + P) (n = 80), or prednisone alone (P) (n = 81) from a Canadian randomized phase III clinical trial. PSA response was defined by > or =50% decline compared to baseline. Palliative response was defined by the primary and secondary endpoints of the trial. All responses were required to be maintained on two visits at least three weeks apart. The Cox proportional hazards model and a landmark analysis (at nine weeks) were used to evaluate survival differences between PSA responders and non-responders. RESULTS: Using an intent-to-treat analysis in which patients with missing PSA data are considered non-responders, 34% of M + P and 11% of P patients achieved a PSA response (P = 0.0001). Nineteen of thirty-six (53%) patients with PSA response and twenty-six of ninety (29%) patients without PSA response achieved a palliative response (P = 0.001 Chi-square test, phi coefficient = 0.28). From the landmark analysis. PSA responders had longer survival than non-responders (P = 0.009). In multivariate analysis, better performance status, higher hemoglobin and PSA response (P < 0.001) predicted for survival, but palliative response did not (P = 0.11). CONCLUSIONS: There is significant but imperfect statistical association between PSA response and palliative response. PSA response was associated with longer survival. Patients treated with M + P were more likely to achieve a PSA response and a palliative response than those treated with P.

Aged↗
PubMed2001

Tumor physiology and drug resistance.

Clinical resistance is usually assumed to be due to the initial presence or selection of drug-resistant cells in tumors. While important, it is suggested in this review that genetically-determined causes of cellular resistance represent but one cause (and possibly not the major cause) of effective clinical resistance of solid tumors. Factors that depend on tumor physiology, and on the microenvironment and three-dimensional structure of solid tumors, may have a profound influence on their sensitivity to anti-cancer drugs. Particular emphasis is placed on the limited penetration of some drugs from tumor blood vessels and on the repopulation of tumor cells between courses of chemotherapy as causes of clinical resistance. Both of these mechanisms are amenable to modulation to improve therapeutic index. Failure to recognize that clinical drug resistance cannot be explained entirely by mechanisms operative at the level of the single cell may lead to disappointing results in clinical trials such as, for example, clinical failure of the strategy of reversal of multidrug resistance.

Animals↗
PubMed2000

The influence of expression of P-glycoprotein on the penetration of anticancer drugs through multicellular layers.

The success of chemotherapy in the treatment of solid tumours may be limited by cellular mechanisms leading to drug resistance and/or by the slow penetration of drugs through tissue, resulting in a steep concentration gradient from tumour blood vessels. One mechanism leading to the development of multidrug resistance is overexpression of the membrane-based export pump P-glycoprotein (P-gp). The relationship between expression of P-gp by constituent cells and the penetration of P-gp substrates through tissue was studied by comparing the penetration of P-gp substrates through multicellular layers derived from either wild-type or P-gp overexpressing cell lines. P-gp reversal agents were added to confirm the contribution of P-gp in influencing the penetration of its substrates. Our data indicate: 1) penetration of the P-gp substrates, 99mTc-sestaMIBI and 14C-doxorubicin, is greater through multicellular layers formed from P-gp overexpressing cell lines as compared with wild-type cells; 2) the addition of agents that inhibit the function of P-gp results in decreased penetration of these substrates through multicellular layers with P-gp expression. There was no effect of P-gp reversal agents on penetration of 14C-sucrose or of 3H-5-fluorouracil (non-substrate controls). Our data suggest that the administration of agents that inhibit the function of P-gp might have opposing effects on therapeutic index in solid tumours: increased sensitivity of perivascular tumour cells but decreased penetration of P-gp substrates to more distal cells. These effects may explain, in part, the limited therapeutic benefit for solid tumours that has accrued from use of agents that reverse the effects of P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Perception of quality of life by patients, partners and treating physicians.

The objective of the study was to determine possible differences in perception of quality of life (QoL) between patients with metastatic breast or prostate cancer, their partners, and the treating physician. Patients with metastatic breast cancer (n = 71), and metastatic prostate cancer (n = 29), a partner, and the physician each completed the same QoL questionnaire indicating how they perceived the patient's QoL. The European organization for research and treatment of cancer (EORTC) QLQ-C30 questionnaire was used to assess patients with breast cancer and the modified prostate cancer specific quality of life instrument (PROSQOLI) for patients with prostate cancer. There was reasonable agreement in mean scores between patients, and physicians or partners, for many domains of QoL; however, there was substantial discordance between scores when considering individual patients. For patients with metastatic breast cancer, physicians systematically underestimated overall QoL (p = 0.0002), social functioning (p = 0.001), and role functioning (p = 0.008), while partners showed better agreement. With prostate cancer physicians tended to underestimate pain, while mean scores for spouses were more concordant. There is substantial variability between ratings of QoL by physicians or partners, as compared to patient ratings. Medical decisions should be based on information about QoL provided by patients using validated methods.

Adult↗
PubMed2000

a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer.

ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.

Adenoviruses, Human↗
PubMed2000

Cognitive function in breast cancer patients receiving adjuvant chemotherapy.

PURPOSE: Breast cancer patients receiving chemotherapy have complained of difficulties in their ability to remember, think, and concentrate. This study assessed whether there are differences in cognitive function between breast cancer patients treated with standard-dose adjuvant chemotherapy compared with healthy controls. PATIENTS AND METHODS: The High Sensitivity Cognitive Screen and the Profile of Mood States (POMS) were used to assess cognitive function and mood in a group of 107 women. The women consisted of 31 breast cancer patients receiving adjuvant chemotherapy (group A), 40 breast cancer patients who had completed adjuvant chemotherapy a median of 2 years earlier (group B), and 36 healthy controls (group C). RESULTS: Univariate analysis showed statistically significant differences (P =.009) in overall cognitive function scores between groups A and C, with poorer function in patients receiving adjuvant chemotherapy. These differences remained significant (P =.046) when controlling for age, education level, and menopausal status. More patients had moderate or severe cognitive impairment in groups A and B than in controls (P </=.002). There were no significant differences in POMS scores between the groups, suggesting that the differences seen in cognitive scores were unlikely to be because of mood disturbance. CONCLUSION: Cognitive differences were observed in breast cancer patients receiving adjuvant chemotherapy compared with healthy controls. These differences did not seem to be caused by significant differences in mood disturbance between the two groups. If confirmed, these results have substantial implications for informed consent, counseling, and psychosocial support of patients receiving adjuvant chemotherapy for breast cancer.

Adult↗
PubMed2000

Prostate specific antigen response to mitoxantrone and prednisone in patients with refractory prostate cancer: prognostic factors and generalizability of a multicenter trial to clinical practice.

PURPOSE: We determine prostate specific antigen (PSA) response and durability, and prognostic factors associated with response and survival in patients with symptomatic hormone refractory prostate cancer treated with mitoxantrone and prednisone at a single institution. We then compare the results with those of a randomized phase III clinical trial. MATERIALS AND METHODS: A retrospective review of all 133 patients treated with mitoxantrone and prednisone at Princess Margaret Hospital since 1994 was performed. PSA response and duration, and overall survival were determined as well as the influence of baseline factors on these outcome parameters. Results were compared to those for patients randomized to receive mitoxantrone and prednisone in the Canadian clinical trial which demonstrated palliative benefit of this regimen. RESULTS: Patients treated after trial closure had shorter survival (p = 0.003) but represented a poorer prognosis cohort. PSA response of the trial and post-trial cases was 34% and 28%, respectively (p = 0.36), and median duration of response was 118 and 175 days or greater, respectively. Factors predictive of PSA response in the non-trial cohort were longer time from diagnosis of prostate cancer (p = 0. 027) and higher baseline PSA (p = 0.013). Factors predictive of increased survival in both groups were younger age (p <0.04), better baseline Eastern Cooperative Oncology Group performance status (p <0. 02), and higher hemoglobin (p </=0.05) and PSA response (p <0.0001). Gleason score was not predictive of response or survival. CONCLUSIONS: Although patients treated outside of the trial had poorer prognostic features, rates of PSA response to mitoxantrone and prednisone were comparable. Factors predictive of survival were similar in the 2 cohorts. Results of the randomized trial are generalizable to clinical practice.

Adenocarcinoma↗
PubMed1999

Influence of cell concentration in limiting the therapeutic benefit of P-glycoprotein reversal agents.

Pharmacological reversal of multidrug resistance (MDR) has been demonstrated frequently in tissue culture, but there has been minimal evidence of therapeutic effectiveness for solid tumours of animals, or in clinical trials. The concentration of cells in solid tumours is approx. 10(9) cells/ml but typically 10(5)-10(6) cells/ml in tissue culture. We investigated, therefore, the influence of cell concentration in culture on the ability of verapamil and cyclosporin A to increase the sensitivity of MDR-expressing cells to doxorubicin. Our data indicate that: 1. the uptake of the MDR substrates, doxorubicin and 99mTc-SestaMIBI, and the toxicity of doxorubicin decrease at higher cell concentration; 2. the effect of reversal agents on uptake and cytotoxicity of MDR substrates decreases markedly at higher cell concentration; 3. cell concentration effects are not overcome by continuous replenishment of drug to maintain a stable extracellular concentration. Our results suggest one mechanism which may contribute to the failure to observe reversal of MDR in animals, or in patients bearing established solid tumours.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1999

Convergent discriminitive, and predictive validity of the Prostate Cancer Specific Quality of Life Instrument (PROSQOLI) assessment and comparison with analogous scales from the EORTC QLQ-C30 and a trial-specific module. European Organisation for Research and Treatment of Cancer. Core Quality of Life Questionnaire.

The Prostate Cancer Specific Quality of Life Instrument (PROSQOLI) is a measure of health-related quality of life (HRQL) that was designed to be an outcome measure for clinical trials in advanced hormone-resistant prostate cancer. The cross-sectional validity of the PROSQOLI was assessed using baseline data from a randomized trial in which HRQL was also assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and a trial-specific quality of life module (QLM-P14). Convergent validity was assessed with the multitrait-multimethod matrix approach; discriminative validity was assessed according to conventional clinical criteria; and predictive validity was assessed by the ability to predict survival duration. These assessments provided strong support for the validity of all PROSQOLI scales except those for family/marriage relationships and passing urine; modifications of these two scales are under evaluation. The strength, consistency, and independence of the prognostic information provided by the HRQL scales were striking. Differences between the instruments were generally subtle. These data support validity of the PROSQOLI and the analogous scales from the QLQ-C30 and QLM-P14 in symptomatic men with advanced hormone resistant prostate cancer. The PROSQOLI is a short, simple, and valid measure of HRQL in this setting.

Analysis of Variance↗
PubMed1999

Third line chemotherapy in patients with metastatic breast cancer: an evaluation of quality of life and cost.

Many patients with metastatic breast cancer receive several types of chemotherapy, although it is recognized that there is a declining probability of response. A major problem confronts oncologists in deciding when to recommend to patients that no further chemotherapy should be given. To address this problem we have assessed prospectively, health-related quality of life (HRQL) and costs of health care for 35 patients with metastatic breast cancer receiving third line chemotherapy in a representative clinical situation. HRQL and utilities were measured longitudinally using the EORTC QLQ-C30 questionnaire and the time trade-off method. Patients received a median of 2 cycles of chemotherapy and lived a median of 4.3 months. Twelve patients (34%) had substantial (> 10 points) improvement in the Global QL subscale and more than 30% of patients had similar changes in emotional and social function. The median baseline utility score was 0.9 and utilities correlated poorly with HRQL subscale. Eighteen patients had measurable disease and one patients experienced a partial response. Grade 3/4 toxicity occurred in 30% of patients. The average cost of management from study entry to death was CDN$ 17,260 (approximately US$ 12,000). Sixteen percent of this cost was associated directly with chemotherapy while hospital admissions and outpatient visits accounted for 50% and 14% of the total cost respectively. We conclude that: (a) many patients receiving third line chemotherapy maintain or improve indices of HRQL despite short survival and a low response rate: this might be due to chemotherapy, placebo effect, or a shift in frame of reference for HRQL; (b) patients were unwilling to trade quantity for quality of life; and (c) response rates and survival may be overestimated in patients selected for clinical trials.

Algorithms↗
PubMed1999

Randomized phase III trial comparing the new potent and selective third-generation aromatase inhibitor vorozole with megestrol acetate in postmenopausal advanced breast cancer patients. North American Vorozole Study Group.

PURPOSE: To compare the efficacy and safety of vorozole (VOR) 2.5 mg once daily with that of megestrol acetate (MA) 40 mg four times per day as second-line therapy in postmenopausal women with advanced breast cancer whose disease progressed after tamoxifen treatment. PATIENTS AND METHODS: A total of 452 patients were enrolled onto an open, multicenter, randomized phase III trial comparing VOR to MA for tumor response, safety, and quality of life (as indicated by the Functional Living Index-Cancer score). RESULTS: Vorozole produced a response rate of 9.7%, compared with 6.8% for MA (P = .24). Clinical benefit (complete response + partial response + no change in > 6 months) was demonstrated in 23.5% and 27.2% of patients treated with VOR and MA, respectively (P = .42). Median duration of response was 18.2 months for VOR versus 12.5 months for MA (P = .074). There was no significant difference in time to progression or survival between the treatment groups. Discontinuation of treatment because of adverse events occurred less frequently in the VOR-treated group (3.1% v 6.2%; P = .18). Patients on the VOR arm reported significantly more nausea, hot flushes, arthralgia, upper respiratory tract infection, anorexia, and paresthesia, whereas those treated with MA had significantly more dyspnea, increased appetite, and weight increase. There was no difference between the two treatment groups in Functional Living Index-Cancer scores (total or subscales). However, when analyzed by objective response, patients with complete or partial responses (P = .032) or no change (P = .033) who were receiving VOR had significant improvement in the psychologic well-being subscale, compared with patients given MA. CONCLUSION: Vorozole is well tolerated and as effective as MA in the treatment of postmenopausal advanced breast cancer patients with disease progression after tamoxifen treatment.

Adult↗
PubMed1999

Cost-utility analysis of chemotherapy using paclitaxel, docetaxel, or vinorelbine for patients with anthracycline-resistant breast cancer.

PURPOSE: Paclitaxel, docetaxel, and vinorelbine have been approved for chemotherapy in patients with advanced breast cancer that is resistant to anthracyclines. Selecting which agent to use is difficult because each possesses advantages and disadvantages related to clinical response, toxicity, method of administration, and cost. A cost-utility analysis was therefore performed to create a rank order on the basis of effectiveness, quality of life, and economic considerations. PATIENTS AND METHODS: Eighty-eight anthracycline-resistant breast cancer patients who had received paclitaxel (n = 34), docetaxel (n = 29), or vinorelbine (n = 25) during the past 2 years were identified. Total resource consumption was collected, which included expenditures for chemotherapy, supportive care, laboratory tests, management of adverse effects, and all related physician fees. Utilities from 25 oncology care providers and 25 breast cancer patients were estimated using the time trade-off technique. The economic estimates from the chart review and clinical data from the literature were then modeled using the principles of decision analysis. RESULTS: Each of the three drugs led to a similar duration of quality-adjusted progression-free survival (paclitaxel, 37.2 days; docetaxel, 33.6 days; vinorelbine, 38.0 days). Vinorelbine was the least costly strategy, with an overall treatment expenditure of Can $3,259 per patient, compared with Can $6,039 and Can $10,090 for paclitaxel and docetaxel, respectively. CONCLUSION: Palliative chemotherapy with vinorelbine in anthracycline-resistant metastatic breast cancer patients has economic advantages over the taxanes and provides at least equivalent quality-adjusted progression-free survival. These benefits are largely related to its lower drug acquisition cost and better toxicity profile.

Adult↗
PubMed1999

Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone.

PURPOSE: A combination of mitoxantrone plus prednisone is preferable to prednisone alone for reduction of pain in men with metastatic, hormone-resistant, prostate cancer. The purpose of this study was to assess the effects of these treatments on health-related quality of life (HQL). PATIENTS AND METHODS: Men with metastatic prostate cancer (n = 161) were randomized to receive either daily prednisone alone or mitoxantrone (every 3 weeks) plus prednisone. Those who received prednisone alone could have mitoxantrone added after 6 weeks if there was no improvement in pain. HQL was assessed before treatment initiation and then every 3 weeks using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) and the Quality of Life Module-Prostate 14 (QOLM-P14), a trial-specific module developed for this study. An intent-to-treat analysis was used to determine the mean duration of HQL improvement and differences in improvement duration between groups of patients. RESULTS: At 6 weeks, both groups showed improvement in several HQL domains, and only physical functioning and pain were better in the mitoxantrone-plus-prednisone group than in the prednisone-alone group. After 6 weeks, patients taking prednisone showed no improvement in HQL scores, whereas those taking mitoxantrone plus prednisone showed significant improvements in global quality of life (P =.009), four functioning domains, and nine symptoms (.001 < P <. 01), and the improvement (> 10 units on a scale of 0 to100) lasted longer than in the prednisone-alone group (.004 < P <.05). The addition of mitoxantrone to prednisone after failure of prednisone alone was associated with improvements in pain, pain impact, pain relief, insomnia, and global quality of life (.001 < P <.003). CONCLUSION: Treatment with mitoxantrone plus prednisone was associated with greater and longer-lasting improvement in several HQL domains and symptoms than treatment with prednisone alone.

Adenocarcinoma↗
PubMed1999

Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (2', 2'-difluorodeoxycytidine) plus cisplatin in previously untreated patients with advanced transitional-cell carcinoma. PATIENTS AND METHODS: Thirty-one patients with measurable advanced transitional-cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1, 8, and 15 and cisplatin 70 mg/m(2) over 1 hour on day 2 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed more than 1 year before study entry. RESULTS: There were six complete responses and 10 partial responses in 28 assessable patients, for an overall response rate of 16 of 28 (57%). The response rate on an intent-to-treat basis was 16 of 31 patients (52%). The median survival is 13.2 months, with 18 patients still alive at this time. Toxicity was primarily hematologic, with 12 of 31 patients (39%) having > or = grade 3 granulocytopenia and 17 of 31 (55%) having > or = grade 3 thrombocytopenia. Two patients had febrile neutropenia. All patients required a dose modification of gemcitabine at some point in their therapy; the primary reason was thrombocytopenia and/or neutropenia. CONCLUSION: Gemcitabine plus cisplatin is an active regimen for the treatment of urothelial cancer.

Adult↗
PubMed1999

Penetration of anticancer drugs through solid tissue: a factor that limits the effectiveness of chemotherapy for solid tumors.

Penetration of anticancer agents to cells distant from the vascular system is required for efficacy of cancer chemotherapy against solid tumors. Many solid tumors have a poorly formed blood vascular system with variable rates of blood flow and much larger intercapillary distances than those found in normal tissues. The requirement for drugs to penetrate several layers of tissue might pose a barrier to the effective treatment of solid tumors. Multicellular layers (approximately 200 microm thick) were grown in vitro on Teflon membranes from EMT6 murine and MCF7 human tumors and have been used to quantitate the penetration of four widely used anticancer drugs through solid tissue. The penetration of doxorubicin and mitoxantrone was limited and very slow (<10% of the rate of penetration through the Teflon membrane alone). The penetration of methotrexate and 5-FU was more rapid (approximately 30-50% of the rate of penetration through the Teflon membrane alone), but remains a substantial barrier to the effectiveness of these drugs. Strategies to improve the penetration of anticancer drugs through poorly vascularized tumor tissue have considerable potential to improve the outcome of chemotherapy for solid tumors.

Animals↗
PubMed1999

The effects of vasodilating drugs on pH in tumors.

Hydralazine has been used widely to reduce tumor blood flow and thereby to induce hypoxia and to reduce extracellular pH (pHe) in tumors. Here we have investigated and compared the effects of the vasodilating drugs hydralazine, captopril, nifedipine, prazosin, sodium nitroprusside, and labetalol to reduce pHe in EMT-6 and KHT tumors of mice and to cause antitumor effects. After a single injection, captopril was most effective in reducing pHe in EMT-6 tumors with a decrease in mean pHe from 6.93 to 6.67 at 2 h after injection, while nifedipine was most effective for KHT tumors with a decrease in mean pHe from 6.96 to 6.75 at 1 h after injection. During 72 h of chronic administration into mice bearing tumors, nifedipine was ineffective in reducing pHe, but both captopril and hydralazine caused a small but significant reduction of pHe. Captopril caused significant delay in growth of the tumors, but had only a small effect on clonogenic cell survival. Captopril appears to be the most effective vasodilating drug to enhance tumor acidity.

Animals↗