Biomedical subjects
Ian F Tannock
Publications and source records attributed to Ian F Tannock.
A phase II trial of continuous low-dose oral cyclophosphamide and celecoxib in patients with renal cell carcinoma.
PURPOSE: The lack of effective systemic therapies for patients with advanced renal cell carcinoma (RCC) has stimulated interest in evaluating novel treatment strategies for this disease. METHODS: This was a two-institution, two-stage, phase II trial of continuous low-dose oral cyclophosphamide (50 mg daily) in combination with celecoxib (400 mg twice daily) in patients with progressive, locally advanced or metastatic RCC. The primary endpoint was disease control rate (DCR) defined as the number of patients with complete (CR) or partial response (PR) or prolonged (> or =6 months) stable disease (SD). Secondary endpoints included time to progression and toxicity. RESULTS: Between May 2001 and January 2003, 36 patients were enrolled onto the trial of which 32 were evaluable for response. One patient had a PR and three others had SD for longer than 6 months (DCR 12.5%, 95% CI 3.5-29.0%). The median progression free survival was 3.5 months (95% CI, 1.9-4.1 months) and the median overall survival was 14.5 months (95% CI, 8.4-20.8 months). One patient experienced grade five gastrointestinal bleeding. Otherwise, the treatment was well tolerated. CONCLUSIONS: Although generally well tolerated, continuous therapy with low-dose cyclophosphamide and celecoxib had limited activity in RCC.
Assessing cognitive function in cancer patients.
GOALS OF WORK: Some patients with cancer suffer cognitive impairment after chemotherapy. A brief, sensitive instrument is required to screen patients for cognitive impairment. In this study, we compare three possible screening instruments. MATERIALS AND METHODS: Cancer patients (n=31) who had received adjuvant chemotherapy within 2 years underwent cognitive evaluation on three occasions. Fluent English speakers (n=20) completed the High Sensitivity Cognitive Screen (HSCS), the computer-based Headminder and CogHealth, and the Functional Assessment of Cancer Therapy-cognitive function (FACT-COG) questionnaire. Patients not fluent in English (NESB) (n=11) performed CogHealth and Headminder. RESULTS: The patients were aged 31-65 years, and 94% were women with breast cancer. At baseline, 6 of 20 (30%) had moderate-severe cognitive impairment on HSCS, 17 of 31 (55%) had scores greater than one standard deviation (SD) below the mean for normative data in one to two of three domains on Headminder, and on CogHealth, 8 of 31 (26%) were greater than one SD below the mean in at least two of six domains. A large practice effect was seen for the HSCS, with moderate-severe cognitive impairment decreasing from 30 to 5% between the first and second assessment. On FACT-COG, 9 of 19 patients (47%) rated their cognition as greater than one SD below that of a pre-chemotherapy breast cancer control group, with impact on quality of life greater than one SD below for 10 of 19 (53%) patients. No correlation was seen between objective cognitive testing and the FACT-COG. CONCLUSIONS: CogHealth and Headminder were suitable for NESB patients. The HSCS is not recommended for longitudinal studies with short intervals between testing due to practice effect. There is poor correlation between the patients' perception of their cognitive impairment and the objective tests.
Scheduling of radiation and chemotherapy for limited-stage small-cell lung cancer: repopulation as a cause of treatment failure?
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The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells.
To reach cancer cells in optimal quantities, therapeutic agents must be delivered to tumors through their imperfect blood vascular system, cross vessel walls into the interstitium, and penetrate multiple layers of tissue. Strategies to enhance drug penetration have potential to improve therapeutic outcome. The development of multicellular layers (MCLs), in which tumor cells are grown on a semipermeable Teflon support membrane, has facilitated quantification of drug penetration through solid tissue. The goals of the present study were to quantify the penetration of anticancer drugs as a function of cellular adhesion and packing density and to determine the effects of variable penetration on therapeutic efficacy in this model system. We compared the properties of MCLs grown from two epithelioid and round subclones of a colon carcinoma cell line. One pair of epithelioid and round sublines differed in expression of alpha-E-catenin, and both pairs generated MCLs with different packing density. The penetration of commonly used anticancer agents (paclitaxel, doxorubicin, methotrexate, and 5-fluorouracil) through MCLs derived from these cell lines was significantly greater through the round (loosely packed) than through the epithelioid (tightly packed) sublines. In MCLs treated with doxorubicin, we observed greater survival in the tightly packed cell lines than in the loosely packed cell lines. Impaired penetration of anticancer agents through MCLs derived from the tightly packed cell lines and relative resistance to killing of cells within them by doxorubicin treatment strengthen the role of tumor cell adhesion and packing density as contributing to drug resistance.
Cognitive function, fatigue, and menopausal symptoms in breast cancer patients receiving adjuvant chemotherapy: evaluation with patient interview after formal assessment.
BACKGROUND: Women who receive adjuvant chemotherapy for breast cancer report fatigue, menopausal symptoms and cognitive problems. Here we compare assessment of these symptoms using self-report questionnaires and a researcher-administered screen of cognitive function with the experience of women as revealed in a semi-structured interview. METHODS: Twenty-one women who were receiving adjuvant chemotherapy completed the Functional Assessment of Cancer Treatment-General (FACT-G) self-report questionnaire, and sub-scales for fatigue (FACT-F) and endocrine symptoms (FACT-ES). They were evaluated for cognitive dysfunction using the High Sensitivity Cognitive Screen (HSCS). They then completed a semi-structured interview, which explored the nature and severity of these symptoms and their impact on daily function. RESULTS: All patients experienced fatigue and most had menopausal symptoms. There was reasonable correlation of findings in the interview with FACT-F and FACT-ES scores. The HSCS revealed fewer problems than were reported by patients, and correlated with patient experience only for the domain of memory. Most patients noted adverse changes in other cognitive domains, especially concentration, with substantial effects on every-day function. CONCLUSIONS: Women receiving adjuvant chemotherapy for breast cancer have substantial problems with fatigue, menopausal symptoms and cognitive changes. Formal tests such as the HSCS may fail to adequately capture the perceived impact of symptoms.
Are prostate cancer clinical trial enrollment criteria and endpoints appropriate?
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Drug penetration in solid tumours.
To be most effective anticancer drugs must penetrate tissue efficiently, reaching all the cancer cells that comprise the target population in a concentration sufficient to exert a therapeutic effect. Most research into the resistance of cancers to chemotherapy has concentrated on molecular mechanisms of resistance, whereas the role of limited drug distribution within tumours has been neglected. We summarize the evidence that indicates that the distribution of many anticancer drugs in tumour tissue is incomplete, and we suggest strategies that might be used either to improve drug penetration through tumour tissue or to select compounds based on their abilities to penetrate tissue, thereby increasing the therapeutic index.
Disseminated intravascular coagulation as the presenting sign of metastatic prostate cancer.
Disseminated intravascular coagulation (DIC) is an acquired coagulation disorder that may occur in a wide variety of clinical conditions. Suspicion of DIC should lead to a differential diagnosis that includes primary fibrinolysis and other bleeding diatheses such as thrombocytopenias of diverse etiology. Confirmation of the diagnosis of DIC should always prompt a search for an underlying medical disorder, including sepsis, severe trauma, solid and hematological malignancies, obstetrical complications, and vascular disorders. Here, we describe an unusual case of acute bleeding and DIC as the presenting manifestation of metastatic prostate cancer in a 60-year-old man. Treatment with a luteinizing hormone-releasing hormone (LHRH) agonist and a short course of an antiandrogen, together with supportive measures (i.e., clotting factors, heparin, and platelets), led to normalization of all coagulation parameters within 1 week, and to clinical improvement and decline in the serum level of prostate-specific antigen (PSA). We discuss the pathogenesis, differential diagnosis, and association of DIC with prostate cancer along with the management of this condition.
The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors.
PURPOSE: Anticancer drugs gain access to solid tumors via the circulatory system and must penetrate the tissue to kill cancer cells. Here, we study the distribution of doxorubicin in relation to blood vessels and regions of hypoxia in solid tumors of mice. EXPERIMENTAL DESIGN: The distribution of doxorubicin was quantified by immunofluorescence in relation to blood vessels (recognized by CD31) of murine 16C and EMT6 tumors and human prostate cancer PC-3 xenografts. Hypoxic regions were identified by injection of EF5. RESULTS: The concentration of doxorubicin decreases exponentially with distance from tumor blood vessels, decreasing to half its perivascular concentration at a distance of about 40 to 50 mum, The mean distance from blood vessels to regions of hypoxia is 90 to 140 microm in these tumors. Many viable tumor cells are not exposed to detectable concentrations of drug following a single injection. CONCLUSIONS: Limited distribution of doxorubicin in solid tumors is an important and neglected cause of clinical resistance that is amenable to modification. The technique described here can be adapted to studying the distribution of other drugs within solid tumors and the effect of strategies to modify their distribution.
Effect of the selective estrogen receptor modulator arzoxifene on repopulation of hormone-responsive breast cancer xenografts between courses of chemotherapy.
Selective inhibition of repopulation of clonogenic tumor cells between courses of chemotherapy has potential to improve the effectiveness of treatment. Here we study arzoxifene, a short-acting selective estrogen receptor modulator, for its potential to inhibit repopulation in estrogen-dependent human breast cancer MCF-7 xenografts between courses of chemotherapy. Proliferation of tumor cells was evaluated by cyclin D1 expression and uptake of 5-bromo-2'-deoxyuridine. Arzoxifene decreased cell proliferation in xenografts. To model adjuvant treatment of human breast cancer, MCF-7 cells were injected s.c. into nude mice and four groups of mice received the following treatments beginning after implantation: (a) control (vehicle solution); (b) arzoxifene alone, 5 days per week by oral gavage for 3 weeks; (c) 5-fluorouracil (5-FU) or paclitaxel i.p. weekly, for 3 doses; and (d) arzoxifene following each cycle of chemotherapy. The incidence of tumors with volume > or =50 mm(3) was determined as a function of time. MCF-7 xenografts developed in 100% of control mice by 4 weeks after implantation. Paclitaxel or 5-FU alone had minor effects to delay the appearance of xenografts whereas arzoxifene alone caused longer delay. Combined treatment with arzoxifene given between cycles of 5-FU or paclitaxel had substantial effects, with approximately 50% tumor incidence by 5 weeks. Our results indicate that arzoxifene can inhibit repopulation of hormone-responsive MCF-7 breast cancer xenografts when given between courses of chemotherapy. The scheduling of short-acting hormonal agents between courses of adjuvant chemotherapy for human breast cancer has potential to improve the outcome of treatment.
Management of advanced prostate cancer after first-line chemotherapy.
Hormone refractory prostate cancer (HRPC) causes substantial morbidity and mortality. There are increasing options for both first- and second-line therapy in the palliative treatment of patients with HRPC. Medications to control symptoms should first be optimized in patients with late-stage disease, and radiotherapy applied to dominant painful bone lesions. Docetaxel, mitoxantrone, satraplatin, and ixabepilone are active chemotherapeutic agents in the first- and/or second-line setting for patients with HRPC, and this may be true also of older drugs such as oral cyclophosphamide and vinorelbine. Radioisotopes such as strontium and samarium are useful for treatment of more generalized bone pain. Third-line hormonal maneuvers including glucocorticoids, ketoconazole, and estrogens can lead to further palliation in some patients, and there are provocative data that chemotherapy might restore hormonal sensitivity in a subset of patients.
Fatigue, menopausal symptoms, and cognitive function in women after adjuvant chemotherapy for breast cancer: 1- and 2-year follow-up of a prospective controlled study.
PURPOSE: We previously evaluated fatigue, menopausal symptoms, and cognitive dysfunction in patients receiving adjuvant therapy for breast cancer and matched healthy women. Here we report assessment of these women 1 and 2 years later. PATIENTS AND METHODS: Patients without relapse and controls were evaluated by the Functional Assessment of Cancer Treatment-General Quality of Life questionnaire, with subscales for fatigue and endocrine symptoms, and by the High Sensitivity Cognitive Screen. RESULTS: There were 104, 91, and 83 patients and 102, 81, and 81 controls assessed at baseline and at 1 and 2 years, respectively. Median Functional Assessment of Cancer Treatment-Fatigue scores (range, 0 to 52) for patients improved from 31 (on chemotherapy) to 43 and 45 at 1 and 2 years, respectively, but were stable in controls (46 to 48). Median Functional Assessment of Cancer Treatment-Endocrine Symptoms scores (range, 0 to 72) for patients improved from 57 (on chemotherapy) to 59 and 61 at 1 and 2 years, respectively, and were stable in controls (64 to 65). Differences between patients and controls remained significant for these scales. The incidence of moderate-severe cognitive dysfunction by the High Sensitivity Cognitive Screen decreased in patients from 16% (on chemotherapy) to 4.4% and 3.8% and in controls from 5% to 3.6% and 0% at 1 and 2 years, respectively. There were minimal differences between estrogen receptor-positive patients who started hormonal therapy (mainly tamoxifen) after chemotherapy and estrogen receptor-negative patients who did not. Differences in quality of life between patients and controls were significant only at baseline. CONCLUSION: Fatigue, menopausal symptoms, and cognitive dysfunction are important adverse effects of chemotherapy that improve in most patients. Hormonal treatment has minimal impact on them.
Should screen-detected breast cancers be managed differently?
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Reduction of intracellular pH as a strategy to enhance the pH-dependent cytotoxic effects of melphalan for human breast cancer cells.
The microenvironment within solid tumors is slightly acidic, and manipulation of this extracellular acidity to cause intracellular acidification might be used to increase selective antitumor effects of some anticancer drugs. Potential mechanisms include inhibition of repair of DNA damage and inhibition of repopulation of tumor cells between successive courses of chemotherapy. Here, we evaluate the influence of extracellular pH (pHe) and of two agents that lead to intracellular acidification (cariporide and S3705) on toxicity of melphalan for two human breast cancer cell lines (MDA-MB231 and MCF7). Both the total number and number of colony-forming cells were evaluated during and after three sequential weekly drug treatments. Our results indicate the following: (a) Slow or absent repopulation after the first course of treatment that is influenced minimally by pHe. (b) Rapid repopulation after the second course of treatment that may be inhibited at low pHe. (c) Effects of low pHe following treatment with melphalan to increase cell kill. (d) Small effects of incubation in cariporide and S3705 at low pHe to increase the net cell kill after treatment with melphalan. Although these results add to evidence that manipulation of intracellular pH within the acidic environment of solid tumors can influence the effects of chemotherapy, they are too small and inconsistent to warrant clinical evaluation.
Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts.
Selective inhibition of repopulation of surviving tumor cells between courses of chemotherapy might improve the outcome of treatment. A potential target for inhibiting repopulation is the mammalian target of rapamycin pathway; PTEN-negative tumor cells are particularly sensitive to inhibition of this pathway. Here we study the rapamycin analogue CCI-779, alone or with chemotherapy, as an inhibitor of proliferation of the human prostate cancer cell lines PC-3 and DU145. The PTEN and phospho-Akt/PKB status and the effect of CCI-779 on phosphorylation of ribosomal protein S6 were evaluated by immunostaining and/or Western blotting. Expression of phospho-Akt/PKB in PTEN mutant PC-3 cells and xenografts was higher than in PTEN wild-type DU145 cells. Phosphorylation of S6 was inhibited by CCI-779 in both cell lines. Cultured cells were treated weekly with mitoxantrone or docetaxel for two cycles, and CCI-779 or vehicle was given between courses. Growth and clonogenic survival of both cell lines were inhibited in a dose-dependent manner by CCI-779, but there were minimal effects when CCI-779 was given between courses of chemotherapy. CCI-779 inhibited the growth of xenografts derived from both cell lines with greater effects against PC-3 than DU145 tumors. CCI-779 caused mild myelosuppression. The activity of mitoxantrone or docetaxel was limited, but CCI-779 given between courses of chemotherapy increased growth delay of PC-3 xenografts. Our results suggest that repopulation of PTEN-negative cancer cells between courses of chemotherapy might be inhibited by CCI-779.
Serum lipids and outcome of early-stage breast cancer: results of a prospective cohort study.
PURPOSE: The prognosis of women with early-stage breast cancer is influenced by insulin and body mass index (BMI). High levels of serum insulin and obesity often coexist with dyslipidemia in the insulin resistance syndrome (IRS), but the contribution of lipids to breast cancer outcome is unclear. Here, we examine whether serum levels of total cholesterol (TC) and triglycerides (TG) influence breast cancer outcome. PATIENTS AND METHODS: A cohort of 520 women without known hyperlipidemia or diabetes, with stage T1-T3, N0-N1, M0 breast cancer, was assembled from July 1989 to June 1996. Fasting blood was collected at baseline. Subjects were followed prospectively, for recurrence (local, regional, distant) and death. Cox models were used to calculate the prognostic effect of TC and TG levels. Two-sided significance levels were set at 0.025. RESULTS: TC was correlated with age (Spearman's r = 0.44) and low tumor grade (p = 0.01), while TG was correlated with insulin (r = 0.43) and BMI (r = 0.45). At a median follow-up of 8.7 years, TC and TG were not associated with breast cancer recurrence or death before of after adjustment for age, tumor-related variables, BMI or fasting insulin levels. In multivariate analysis adjusting for age, tumor-related variables and BMI, a trend towards an adverse effect of TC on disease recurrence was seen (HR recurrence = 1.62 for the 4th versus. 1st quartile, 2-sided p = 0.03). CONCLUSIONS: Fasting TG was not associated with outcome. A trend towards risk of recurrence was seen with higher TC in multivariate analysis. This potential association should be explored in future studies.