Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404

Prados, Michael D.; Seiferheld, W.; Sandler, Howard M.; Buckner, Jan C.; Phillips, Theodore L.; Schultz, Christopher J.; Urtasun, Raul C.; Davis, Richard L.; Gutin, Philip H.; Cascino, Terrence L.; Greenberg, Harry S.; Curran, Walter J.

doi:10.1016/j.ijrobp.2003.08.024

Cited by 119 publications

(50 citation statements)

References 12 publications

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“…15 For newly diagnosed anaplastic astrocytomas, a study by the Radiation Therapy Oncology Group 16 showed that patients with no progression at 6 months had a median survival of 67 months versus a median survival of 19 months for patients who had shown progression by 6 months. Thus, for anaplastic gliomas, there is evidence that response to initial treatment correlates with survival.…”

Section: Validity Of Imaging End Points In Clinical Trialsmentioning

confidence: 99%

Brain Tumor Imaging in Clinical Trials

Henson

Ulmer

Harris

2008

AJNR Am J Neuroradiol

160

108

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SUMMARY:There are substantial challenges in the radiologic evaluation of tumor size during clinical trials, and it is important for neuroradiologists to have a firm understanding of these issues. This review will examine measurement approaches, response criteria, selection of lesions for measurement, technical imaging considerations, interval between tumor measurements and response confirmation, and validity of imaging as a measure of efficacy.

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Section: Validity Of Imaging End Points In Clinical Trialsmentioning

confidence: 99%

Brain Tumor Imaging in Clinical Trials

Henson

Ulmer

Harris

2008

AJNR Am J Neuroradiol

160

108

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“…BrdU was subsequently found to be a potent radiosensitizer and photosensitizer [1][2][3], and trials using combined chemotherapies that include BrdU as a radiosensitizer continue today [4]. BrdU incorporation into DNA results in several types of DNA lesions, including mutations [5], fragile sites [6], chromatid breaks [7] and sister chromatid exchanges [8].…”

Section: Introductionmentioning

confidence: 99%

5-Bromo-2-deoxyuridine activates DNA damage signalling responses and induces a senescence-like phenotype in p16-null lung cancer cells

Masterson

O’Dea

2007

Anti-Cancer Drugs

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5-Bromo-2-deoxyuridine (BrdU) is a thymidine analogue that is incorporated into replicating DNA. Although originally designed as a chemotherapeutic agent, sublethal concentrations of BrdU have long been known to alter the growth and phenotype of a wide range of cell types. Mechanisms underlying these BrdU-mediated effects remain unknown, however. We have characterized the effects of BrdU on A549 lung cancer cells by examining DNA damage responses, cell cycle effects and phenotypic changes. A549 cells express wild-type p53, but are p16-null. Sublethal concentrations of BrdU evoke a DNA damage response in these cells that involves the activation of Chk1, Chk2 and p53. Increased numbers of enlarged nuclei and multinucleated cells are evident in the treated populations. Cell cycle inhibition occurs, resulting in reduced proliferation and accumulation of cells in the S, G 2 /M and G 0 phases. BrdU induces an early inhibition of p21 expression that coincides with nuclear localization of proliferating cell nuclear antigen. Subsequently, p21 levels increase, whereas proliferating cell nuclear antigen levels decrease compared with control cells. Upregulation of p27 and p57 expression also occurs. By day 7 of exposure to BrdU, treated cells acquire a senescent-like phenotype with an increase in cell size, granularity and bgalactosidase activity. We conclude that BrdU induces a DNA damage response in A549 cells, which results in reduced proliferation mitotic exit and phenotypic changes that resemble senescence.

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“…Moreover, the survival time for patients with anaplastic astrocytomas was only 13 months, much shorter than typically had been observed in previous clinical trials. For example, a different large clinical trial conducted to test the effect of a radiation sensitizer (which failed to provide a benefit) reported a median survival time of 45 months (Prados et al 2004).…”

Section: Perils Of Evidence-based Medicinementioning

confidence: 99%

Perils of Evidence-Based Medicine

Williams¹

2010

pbm

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Evidenced-based medicine views random-assignment clinical trials as the gold standard of evidence. Because patient populations are heterogeneous, large numbers of patients must be studied in order to achieve statistically significant results, but the means or medians of these large samples have weak predictive validity for individual patients. Further, the logic of random-assignment clinical trials allows only the inference that some subset of patients benefits from the treatment. Post-hoc analysis is therefore necessary to identify those patients. Otherwise, many patients may receive treatments that are useless and potentially harmful. M EDICINE HAS AVIDLY EMBRACED evidence-based medicine: best medical practices should be determined not by the experience of the individual clinicians, nor by the accumulated wisdom of clinicians more generally, but by the results of well-controlled clinical trials.Yet despite its increasing dominance in medical education, evidence-based medicine (EBM) has received considerable criticism, especially from philosophers of science who have questioned the central tenet that randomized trials should be the primary basis for establishing clinical practice (e.g., Bluhm 2005;Borgerson 2009;Goldenberg 2009;Grossman and Mackenzie 2005). Because this claim about randomized trials is essentially pragmatic in nature, it must be justified by a demonstration that better clinical outcomes result from randomized trials than from other types of clinical evidence. In fact, however, no such demonstration has been provided.Whereas criticisms by philosophers of science have focused on the justifica-

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Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404

Cited by 119 publications

References 12 publications

Brain Tumor Imaging in Clinical Trials

Brain Tumor Imaging in Clinical Trials

5-Bromo-2-deoxyuridine activates DNA damage signalling responses and induces a senescence-like phenotype in p16-null lung cancer cells

Perils of Evidence-Based Medicine

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