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Clinical Investigations |
Division of Biostatistics (K.V.B., B.R.L.), Division of Medical Oncology (J.C.B.), Department of Radiation Oncology (P.D.B.), and Department of Pathology (C.G.), Mayo Clinic College of Medicine, Rochester, MN; Metro-Minnesota Community Clinical Oncology Program (P.J.F.), St. Louis Park, MN; and Department of Neurology (K.A.J.), Mayo Clinic, Jacksonville, FL; USA
1 Address correspondence to Karla Ballman, Ph.D., Mayo Clinic, Division of Biostatistics, 200 First Street SW, Rochester, MN 55905, USA (ballman{at}mayo.edu).
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Abstract |
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Key Words: end points • glioblastoma multiforme • phase II clinical trials
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Introduction |
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Phase II studies are limited because they lack a control arm and rely on a historical value as a comparison for treatment efficacy. It is therefore crucial that patients enrolled on a phase II trial are representative of the patient population from which the historical comparison value was obtained, because both end points would otherwise suffer from patient selection bias. Beyond this, there are advantages and limitations for both PFS6 and OS12. OS12 is objectively ascertained. One drawback of using OS12 is that it could potentially be influenced by life-prolonging subsequent therapy administered after patients leave the study (typically, upon progression); additionally, investigators must wait at least 12 months from the time of last patient enrollment before the study results are known. On the other hand, PFS6 directly measures the efficacy of initial therapy, unaffected by treatment at progression. When PFS6 is the end point, study results can be obtained six months sooner than when OS12 is used. The drawback is that PFS6 is based on clinical and/or imaging criteria, both which have an element of subjectivity (e.g., progression erroneously declared) and may be influenced by prior therapies (e.g., surgery, radiotherapy, intratumoral therapy, and corticosteroids), imaging technique, and observer subjectivity.
In this study, our primary goal was to determine the relationship between PFS6 and OS12 as end points in phase II GBM trials. A secondary goal was to determine the relationship between PFS6 and the true end point of overall survival (the assumed gold standard). We were also interested in whether the relationships assessed in our primary and secondary goals were similar for patients with newly diagnosed GBM and those with recurrent disease. Knowing these relationships will enable investigators to make more informed choices between OS12 and PFS6 as outcomes in phase II trials for GBM patients. We aggregated all GBM patients that were treated on a North Central Cancer Treatment Group (NCCTG) protocol and stratified our analysis by patients with newly diagnosed GBM and by those with recurrent disease.
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Methods |
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General characteristics of the 11 trials that enrolled patients with newly diagnosed GBM and the 16 trials that enrolled patients with recurrent GBM are reported in Table 1. Results for all trials were deemed negative by the primary end point decision criterion; that is, no improvement over the historical experience was found in phase II trials, and no significant difference in the primary end points was observed among the treatment arms in phase III trials.
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Patient Eligibility
Newly Diagnosed GBM. Patient eligibility was similar across the trials that enrolled patients with newly diagnosed GBM. All patients underwent a biopsy and/or tumor resection prior to study enrollment, and central pathology review was performed in all cases. Only patients with histologically identified GBM were used in our analysis. Patients were not allowed to enroll until they recovered from their biopsy or surgery but were required to enroll within six to eight weeks of their biopsy or surgery. For most trials, patients had to be adults (
18 years old) and had to have an Eastern Cooperative Oncology Group performance score (PS) of 2 or less. Patients were not eligible if they had prior chemotherapy for a brain tumor. All patients received radiotherapy, and all trials involved chemotherapy.
Recurrent GBM. Likewise, patient eligibility criteria were similar across the protocols that enrolled patients with recurrent GBM. All trials required evidence of recurrence after prior radiotherapy. For most studies, the age criterion (18 years old) and PS criterion (PS 
2) were the same as for trials of newly diagnosed patients. Prior chemotherapy regimens were allowable. Patient enrollment was allowed if it had been 8-12 weeks or longer since the completion of radiotherapy and four to six weeks or longer since the completion of chemotherapy for GBM. Only patients with histologically identified GBM, either at initial diagnosis or at recurrence as confirmed by central pathology review, were eligible for this study.
Treatment Evaluation and Event-Monitoring Schedules
All NCCTG trials of patients with newly diagnosed or recurrent GBM had equivalent evaluation schedules. Generally, patients were evaluated every two months during the active-monitoring phase (i.e., while receiving study treatment). An evaluation included a neurologic examination and an imaging study (either CT or MRI); the same imaging modality was used consistently on a patient throughout the study. When patients completed or went off study treatment (e.g., because of disease progression, refusal of further treatment, or toxicity), they entered an event-monitoring phase. Patients remained in event monitoring until death or the end of study.
Tumor progression was determined by a combination of the neurologic examination status and imaging results. An imaging progression occurred when there was a greater than 25% increase in the product of perpendicular diameters of contrast enhancement or mass (compared with pretreatment scan) for bidimensionally measurable disease or an unequivocal increase in the size of contrast enhancement or increase in mass effect (compared with pretreatment scan), as agreed upon independently by the primary physician and quality-control physicians for evaluable disease (i.e., contrast-enhancing mass on CT/MRI that is not measurable but clearly evaluable for response to therapy). For both measurable and evaluable tumors, the appearance of new lesions signified disease progression regardless of the status of the initial tumor. The neurologic examination status was deemed better, same, or worse compared with the pretreatment examination. A patient was identified as having disease progression when there was progression by the imaging study and the neurologic examination status was determined as the same or worse. If there was a discrepancy between the neurologic status examination and CT/MRI measurement (i.e., neurologic examination status was better but CT/MRI indicated disease progression, or neurologic examination status was worse but CT/MRI did not indicate progression), the patient continued treatment until the next evaluation. If the discrepancy remained, the patient was classified as having disease progression at the time of the subsequent evaluation.
Statistical Considerations
Summary statistics used for categorical variables were the frequency and percent. Those used for continuous variables were the mean ± 1 SD and the median and range (minimum to maximum values). Survival curves were estimated with the Kaplan-Meier estimates (Kaplan and Meier, 1958) and compared using the log-rank test (Peto and Peto, 1972). Survival experiences were summarized with the median value and 95% CI.
Patient-level agreement between the PFS6 and the OS12 end points meant that a patient was progression free at six months and alive at 12 months or that a patient had disease progression by six months and was dead by 12 months. The patient-level agreement was summarized by the raw agreement, the number of patients for which the end points agreed divided by the total number of patients. Furthermore, the expected levels of agreement due to chance alone were also determined. A kappa statistic (Cohen, 1968) and 95% CI were used to summarize the amount of agreement above and beyond that expected by chance alone. One can interpret a kappa statistic as a type of correlation coefficient. It ranges from 0 (no agreement) to 1 (perfect agreement). Values observed in the 0.4-0.6 range indicate moderate agreement, those in the 0.6-0.8 range indicate substantial agreement, and those in the 0.8-1.0 range indicate strong agreement.
Study-level agreement was assessed with two methods: The first was the determination of the association between the study PFS6 proportion and OS12 proportion, and the second was a measure of agreement of the overall study decision between using a PFS6 end point and an OS12 end point. The first method used weighted linear regression in which the numbers of patients in the study were the weights, thus giving more weight to studies with more patients. The equation of the regression line is given; if there was perfect agreement between the values of the two end-point values per study, the slope of the line would be 1 and the intercept would be 0. In addition, the value of the correlation coefficient was also computed and reported. Note that the correlation coefficient is somewhat dependent on the range of observed values for the independent variable. Even in cases in which variables are strongly correlated, when the relationship is assessed over a small portion of the potential range, the correlation value will be less than when assessed over the entire range.
Because of the small number of studies and small sample sizes for some studies, we used simulation to explore the agreement at the study level between the two end points. Of particular interest was the amount of agreement between the study decisions when using the PFS6 end point versus the OS12 end point. To assess this, we replicated our current approach for designing phase II clinical trials. We computed the historical control values of PFS6 and OS12 to be used in our phase II trial designs based on the observed outcomes of our database of 1348 patients with newly diagnosed GBM and 345 patients with recurrent GBM: PFS6 and OS12 values were 43% and 41%, respectively, for newly diagnosed cases and 9% and 14%, respectively, for recurrent cases. For each patient group, we designed a two-stage phase II study using a Simon design (Simon, 1989). The level of significance used was 0.10, and there was 0.90 power to detect a minimum increase of 0.15 above the historical control value. The required sample size for the patients with newly diagnosed GBM was n = 83 patients for both the PFS6 and OS12 end points, and the required sample sizes for the patients with recurrent GBM was n = 53 for both end points. We performed a simulation of 10,000 trials for each patient group. Specifically, for each trial, we selected the required number of patients with replacement from the pooled data. Using the observed progression-free survival and overall survival times for each patient, we determined their PFS6 status and OS12 status. On the basis of these, we determined the study final decision (including the possibility for stopping because of futility after the first stage)—that is, sufficient evidence to warrant further investigation versus no evidence of activity, meaning the regimen does not merit further investigation. In each case, we recorded whether the two study end points agreed at the end of each simulation. We then computed the percentage of trials for which there was agreement in the final study decision between the two end points. This is in the spirit of a criterion advocated by Begg and Leung (2000) for determining whether one end point is a good surrogate for another.
PFS6 is merely a potential surrogate end point for the real quantity of interest: overall survival. A good surrogate needs to be correlated with the end point it is intended to replace, although this is not a sufficient condition. To assess the relationship between PFS6 and overall survival, we used Cox proportional hazard modeling. The outcome was overall survival, and the timedependent covariate was progression status (disease progression vs. no progression). Conceptually, this means that, at the beginning of the trial, all of the patients were in the no-progression group. When patients experienced documented disease progression, they switched from the no-progression group to the progression group. Patients who died without a documented disease progression were censored for death at the time of their last evaluation for progression; patients without documented disease progression and with documentation of a death due to a cause other than their GBM were not censored. We generated separate models for the patient groups with newly diagnosed and recurrent GBM. Furthermore, we compared the survival experience of patients who were deemed progressors at six months with the experience of those who did not have disease progression at six months. We employed a conservative approach for this analysis and used only those patients who were alive and not censored at six months. For the purposes of this analysis, not censored means their follow-up (including their last tumor evaluation) was six months or longer. Again, separate analyses were performed for patients with newly diagnosed GBM and those with recurrent disease.
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Results |
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There were 16 trials for patients with recurrent or progressive brain tumors, which included 345 patients with recurrent GBM. These studies enrolled patients between June 1980 and September 2004. The median number of patients enrolled on a study was 17 (range, 1-68). Of the 345 patients, 277 (80%) were enrolled on phase II trials, and 68 (20%) were enrolled on phase III trials. Results for all these trials were also declared negative, meaning they did not meet the predefined efficacy criteria. At present, almost all patients (328 of 345) have died, and 39 (11%) died without documented disease progression prior to death. This percentage is similar to that for the patients with newly diagnosed GBM.
The average age (±SD) at trial entry was 57 ± 12 years for patients with newly diagnosed GBM and 53 ± 12 years for patients with recurrent GBM, and 61% of the patients in both groups were men (Table 2). The PS value was 0 in a considerably greater fraction of patients with newly diagnosed disease compared with patients with recurrent disease (30% compared with 16%, respectively), and a considerably greater fraction of patients with recurrent GBM had a PS of 2 compared with patients with newly diagnosed GBM (36% compared with 16%). The patients with recurrent GBM were more likely to have had a gross total resection upon initial diagnosis than were the patients with newly diagnosed disease (33% compared with 19%). Finally, a large majority of patients with recurrent GBM (72%) did not undergo resection or biopsy at the time of recurrence or progressive disease.
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Appropriateness of PFS6 End Point
Figure 1 shows the survival and progression-free survival curves. The median survivals were 10.2 months (95% CI, 9.7-10.7 months) for patients with newly diagnosed GBM and 5.0 months (95% CI, 4.6-5.4 months) for patients with recurrent GBM. Median progression-free survival times were 5.3 months (95% CI, 5.0-5.6 months) for patients with newly diagnosed GBM and 1.8 months (1.7-2.0 months) for patients with recurrent disease.
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Study-Level Agreement
Weighted linear regression was used to assess the strength of the relationship between the observed proportion of PFS6 patients (explanatory variable) and OS12 (outcome variable) for the 11 trials of patients with newly diagnosed GBM and the 16 trials of patients with recurrent GBM. The regression line for the patients with newly diagnosed GBM was OS12 = 0.24 + 0.40 x PFS6 (Fig. 4A). There was a positive linear relationship between the end points, although it did not quite achieve statistical significance (P for the slope = 0.09). The correlation coefficient value was r = 0.53. Overall, the observed relationship was only moderately strong. In particular, the slope of the line was 0.40, which differed significantly from 1 (P = 0.02), and the correlation was only 0.53, which indicates that only 28% of the variation in the observed OS12 rates was explained by the PFS6 rates. A partial explanation for the poor correlation is that most of the larger studies span only a relatively small range of the observed progression-free survival values (between 0.25 and 0.50). Specifically, low correlation values are often observed when the values on the horizontal axis span only a small range of potential values.
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For the patients with recurrence, the equation of the weighted regression line was OS12 = 0.08 + 0.61 x PFS6, and the corresponding correlation coefficient was 0.64. There was a significant positive relationship between the two end points (P for the slope = 0.01), although there was some evidence that the slope differed from 1 (P = 0.07). As for the patients with newly diagnosed GBM, the strength of the relationship was at most moderate. The observed values were slightly higher for the patients with recurrent versus newly diagnosed disease, with a slope closer to 1.0 and a higher correlation coefficient. As for the patients with newly diagnosed GBM, the observed PFS6 rates span only a small fraction of the potential values for the majority of the studies (i.e., 0-0.15). There is one potentially influential study (a PFS6 rate of approximately 0.45) that could have artificially inflated the observed correlation value. The correlation value with this study removed was 0.47.
Overall, the relationships between PFS6 and OS12 for patient trials of newly diagnosed GBM and of recurrent GBM were positive, which is as expected. However, the relationships were of moderate strength, meaning that if we know the PFS6 value for a trial, we would not be able to predict accurately what its OS12 value would be. This is a little surprising but likely explained by the observed range of values for PFS6 being relatively limited.
Study Decision Agreement
To assess the number of times the study decision based on a PFS6 end point agrees with the study decision based on an OS12 end point, we performed the simulation studies described in the Statistical Considerations section. For the trials of newly diagnosed disease, there was agreement in 88% of the simulated trials between the PFS6 and OS12 end points. For the trials of recurrent GBM, there was 90% agreement between studies designed with the OS12 and PFS6 end points. In both patient groups, the simulations resulted in a substantially high level of agreement in study decisions between these two end points.
Relationship Between Progression and Overall Survival
Another important aspect of interest is the relationship between progression and the true end point of interest: overall survival. This was assessed in two ways: using progression as a time-dependent variable, and comparing the survival experiences between patients who were alive at six months and progression free and those who were alive at six months and had disease progression prior to then. For patients with newly diagnosed GBM, the hazard ratio for progression treated as a time-dependent variable was 16.2 (95% CI, 13.2-19.8). This indicates quite a strong relationship between progression and survival. For patients who were alive at six months (n = 1002), we compared the survival experience between those patients who had disease progression by six months and those patients who were progression free at six months. The estimate of the hazard ratio was 2.1 (95% CI, 1.8-2.4), indicating that patients who had disease progression by six months were approximately twice as likely to die within a given time period as those patients who had not had progression by six months. The survival curves for the two groups differed significantly (Fig. 5A): median survival (measured from six months after study entry) was 8.6 months for the nonprogressors and 3.8 months for progressors (P < 0.001). The results were similar for the patients with recurrent GBM. The hazard ratio for progression treated as a time-dependent variable was 8.5 (95% CI, 5.7-12.8). Only 129 patients were alive at six months. The hazard ratio for those who had disease progression by then and those who had not was 2.4 (95% CI, 1.6-3.8). Again, the likelihood of death for individuals who had disease progression by six months was more than twice that for patients without progression. The median remaining survival time for patients who had progression by six months was 3.3 months compared with 11.6 months for those without progression by six months (P < 0.001; Fig. 5B).
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Discussion |
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Few publications have compared the relationship between PFS6 and OS12 in glioma trials. Investigators advocate the use of a progression-free end point in phase II trials rather than a response end point when evaluating the cytostatic therapeutics (Batchelor et al., 2001; Brada and Yung, 2000; Mick et al., 2000). However, it is recognized that the ultimate goal is to increase overall survival. Some comparisons have been made between progression-free (or disease-free)-based and survival-based end points in other solid tumors. Sekine et al. (1999) found that the rate of progressive disease was significantly correlated with the median survival time; the correlation was higher than that between the response rate and median survival time. Sargent et al. (2005) completed a formal evaluation of a disease-free primary end point versus an overall survival end point. They concluded that, in adjuvant colon cancer trials of fluorouracil-based regimens, disease-free survival after three years of median follow-up is an appropriate end point.
The relationship between a potential surrogate end point and the true end point should be analyzed on several levels. Merely assessing the relationship between progression-free survival and survival using study-level summary statistics could potentially be misleading (Buyse and Pascal, 1996). A serious problem is that it is extremely likely that progression-free survival and survival are affected by the same factors (known or unknown), so any relationship observed between progression-free survival and overall survival in different studies may be mediated by these confounding factors. As a consequence, it is also important to ascertain the strength of the relationship at the patient level. Furthermore, it has been argued that the surrogate end point must be strongly associated or correlated with the true end point (Begg and Leung, 2000), although a strong correlation between the end points is not by itself sufficient for determining the adequacy of a surrogate (Baker and Kramer, 2003).
In this study, we evaluated the relationship between PFS6 and OS12 at all three levels: patient level, study level, and correlation/concordance of study end results. It appeared as though the agreement at both the study level and patient level is at most moderate for both the recurrent GBM and the newly diagnosed GBM cohorts. However, the study decision outcomes from our simulation analyses had relatively high agreement. Furthermore, there was a substantial difference in overall survival between patients who had disease progression by six months and those who had not, as well as a large hazard ratio between progression-free survival and overall survival in the time-dependent Cox regression analysis. Overall, the relationship between PFS6 and OS12 appeared slightly stronger in the patients with recurrent GBM than in patients with newly diagnosed disease. A progression-free survival evaluation at six months also seemed to capture more of the OS12 event information for the recurrent cases than for the newly diagnosed cases (Fig. 2), which is supported by the larger difference in median survival times between six-month progressors and nonprogressors in the recurrent group.
It should be understood that our analysis is not a formal analysis of the adequacy of PFS6 as a surrogate for OS12. Such an analysis would require a large amount of patient-level data from multiple phase III studies. In addition, our analysis is somewhat limited by the fact that results for all the trials were negative. As a consequence, the relationship between these two end points could differ for trials with positive results. In particular, for a trial with a positive result, OS12 might be improved while PFS6 is unaffected, or PFS6 might be improved and OS12 unaffected.
An increasingly important role of a phase II trial is to provide information on the effects of therapy on a biologic or molecular level. This is especially true for targeted therapeutics. If a phase II trial measures only potential survival benefit, an agent that has activity on the biologic or molecular level might be wrongfully discarded. Obviously an active agent that does not demonstrate potential benefit would not be ready for a phase III trial. However, if the phase II trial could provide information that aids in understanding the nature of the molecular and biologic activity, this would be valuable in determining future combination therapies using this agent or in identifying subgroups of patients for which this agent is active. To achieve this goal, it is essential to use phase II designs that provide the necessary secondary end points for assessing the molecular and biologic activity of a therapy, such as the end points proposed by Lang et al. (2002).
Given that GBM survival experience is similar to that with late-stage disease, it is feasible to obtain a preliminary estimate of treatment efficacy from survival-based end points in a reasonable amount of time, providing investigators with a sound understanding of how the treatment will affect survival prior to the initiation of a large phase III trial. In light of our assessment of the relationship between PFS6 and OS12, it appears that PFS6 provides only a moderately reliable estimate of survival. For patients with newly diagnosed GBM, it seems judicious to use an OS12 end point. Using a PFS6 end point saves only about six months out of a complete process that requires a total of two to three years (from study concept to mature data) at the cost of a less reliable estimate of the true survival end point, which is what will be used in a subsequent phase III trial. This assumes that statistical power would be the same using the same number of patients for both end points, as was essentially true for our data. The time savings could be less or more in the future, depending on changes in the historical control values for PFS6 and OS12. The trial with the historical control value closer to 0.50 would require more patients. On the other hand, agents that are found to have activity in phase II trials for recurrent GBM are often brought forward to a phase II trial for patients with newly diagnosed GBM, either as an agent used concurrently with radiotherapy or as adjuvant treatment. Furthermore, a six-month time point for the progression-free survival evaluation in recurrent gliomas captured more OS12 information than in newly diagnosed cases. Thus, it seems reasonable to use PFS6 as the primary end point in trials of recurrent GBM.
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Footnotes |
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Received for publication June 1, 2006. Accepted for publication September 1, 2006.
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References |
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Baker, S.G., and Kramer, B.S. (2003) A perfect correlate does not a surrogate make. BMC Med. Res. Methodol. 3, 16.[CrossRef][Medline]
Batchelor, T., Stanley, K., and Andersen, J. (2001) Clinical trials in neurooncology. Curr. Opin. Neurol. 14, 689-694.[CrossRef][Web of Science][Medline]
Begg, C.B., and Leung, D.H.Y. (2000) On the use of surrogate end points in randomized trials. J. R. Stat. Soc. A 163(pt. 1), 15-28.[CrossRef]
Brada, M., and Yung, W.K.A. (2000) Clinical trial end points in malignant glioma: Need for effective trial design strategy. Semin. Oncol. 27(suppl. 6), 11-19.[Web of Science][Medline]
Buckner, J.C., Brown, L.D., Cascino, T.L., Gerstner, J.B., Krook, J.E., Westberg, M.W., Wiesenfeld, M., O'Fallon, J.R., and Scheithauer, B. (1990) Phase II evaluation of infusional etoposide and cisplatin in patients with recurrent astrocytoma. J. Neurooncol. 9, 249-254.[Medline]
Buckner, J.C., Brown, L.D., Kugler, J.W., Cascino, T.L., Krook, J.E., Mailliard, J.A., Kardinal, C.G., Tschetter, L.K., O'Fallon, J.R., and Scheithauer, B.W. (1995) Phase II evaluation of recombinant interferon alpha and BCNU in recurrent glioma. J. Neurosurg. 82, 430-435.[Web of Science][Medline]
Buckner, J.C., Burch, P.A., Cascino, T.L., O'Fallon, J.R., and Scheithauer, B.W. (1998) Phase II trial of recombinant interferon-alpha-2a and eflornithine in patients with recurrent glioma. J. Neurooncol. 36, 65-70.[CrossRef][Medline]
Buckner, J.C., Michalak, J.C., Schomberg, P.J., Burton, G.V., Sandler, H.M., Cascino, T.L., Hawkins, R.B., Scheithauer, B.W., and O'Fallon, J.R. (2001a) Phase III trial of BCNU plus cisplatin (CDDP) versus BCNU alone, and standard radiation therapy (SRT) versus accelerated radiation therapy (ART) in glioblastoma (GBM) patients (Pts): NCCTG/SWOG results. Proc. Am. Soc. Clin. Oncol. 20, 51a (abstract 202).
Buckner, J.C., Schomberg, P.J., McGinnis, W.L., Cascino, T.L., Scheithauer, B.W., O'Fallon, J.R., Morton, R.F., Kuross, S.A., Mailliard, J.A., Hatfield, A.K., Cole, J.T., Steen, P.D., and Bernath, A.M. (2001b) A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma. Cancer 92, 420-433.[CrossRef][Web of Science][Medline]
Burch, P.A., Bernath, A.M., Cascino, T.L., Scheithauer, B.W., Novotny, P., Nair, S., Buckner, J.C., Pfeifle, D.M., Kugler, J.W., and Tschetter, L.K. (2000) A North Central Cancer Treatment Group phase II trial of topotecan in relapsed gliomas. Invest. New Drugs 18, 275-280.[CrossRef][Web of Science][Medline]
Buyse, M., and Pascal, P. (1996) On the relationship between response to treatment and survival time. Stat. Med. 15, 2797-2812.[CrossRef][Web of Science][Medline]
Cascino, T.L., Brown, L.D., Morton, R.F., Everson, L.K., Marschke, R.F., Dinapoli, R.P., and O'Fallon, J.R. (1988) Evaluation of fludarabine phosphate in patients with recurrent glioma. Am. J. Clin. Oncol. 11, 586-588.[Web of Science][Medline]
Cascino, T.L., Veeder, M.H., Buckner, J.C., O'Fallon, J.R., Wiesenfeld, M., Levitt, R., Goldberg, R.M., Kuross, S.A., Morton, R.F., and Scheithauer, B.W. (1996) Phase II study of 5-fluorouracil and leucovorin in recurrent primary brain tumor. J. Neurooncol. 30, 243-246.[Medline]
Cohen, J. (1968) Weighted kappa: Nominal scale agreement with provision for scaled disagreement or partial credit. Psychol. Bull. 70, 213-220.[CrossRef][Medline]
Dinapoli, R.P., Brown, L.D., Arusell, R.M., Earle, J.D., O'Fallon, J.R., Buckner, J.C., Scheithauer, B.W., Krook, J.E., Tschetter, L.K., and Maier, J.A. (1993) Phase III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma. J. Clin. Oncol. 11, 1316-1321.
Elliott, T.E., Buckner, J.C., Cascino, T.L., Levitt, R., O'Fallon, J.R., and Scheithauer, B.W. (1991) Phase II study of ifosfamide with mesna in adult patients with recurrent diffuse astrocytoma. J. Neurooncol. 10, 27-30.[CrossRef][Medline]
Elliott, T.E., Dinapoli, R.P., O'Fallon, J.R., Krook, J.E., Earle, J.D., Morton, R.F., Levitt, R., Tschetter, L.K., Scheithauer, B.W., Pfeifle, D.M., Twito, D.I., and Nelimark, R.A. (1997) Randomized trial of radiation therapy (RT) plus dibromodulcitol (DBD) versus RT plus BCNU in high grade astrocytoma. J. Neurooncol. 33, 239-250.[CrossRef][Medline]
Fazzari, M., and Heller, G. (2000) The phase II/III transition: Toward the proof of efficacy in cancer clinical trials. Control. Clin. Trials 21, 360-368.[CrossRef][Web of Science][Medline]
Galanis, E., Buckner, J.C., Burch, P.A., Schaefer, P.L., Dinapoli, R.P., Novotny, P.J., Scheithauer, B.W., Rowland, K.M., Vukov, A.M., Mailliard, J.A., and Morton, R.F. (1998) Phase II trial of nitrogen mustard, vincristine, and procarbazine in patients with recurrent glioma: North Central Cancer Treatment Group results. J. Clin. Oncol. 16, 2953-2958.
Galanis, E., Buckner, J.C., Maurer, M.J., Kreisberg, J.I., Ballman, K., Boni, J., Peralba, J.M., Jenkins, R.B., Dakhil, S.R., Morton, R.F., Jaeckle, K.A., Scheithauer, B.W., Dancey, J., Hidalgo, M., and Walsh, D.J., for the North Central Cancer Treatment Group (2005a) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A North Central Cancer Treatment Group Study. J. Clin. Oncol. 23, 5294-5304.
Galanis, E., Buckner, J.C., Maurer, M.J., Reid, J.M., Kuffel, M.J., Ames, M.M., Scheithauer, B.W., Hammack, J.E., Pipoly, G., and Kuross, S.A. (2005b) Phase I/II trial of pyrazoloacridine and carboplatin in patients with recurrent glioma: A North Central Cancer Treatment Group trial. Invest. New Drugs 23, 495-503.[CrossRef][Web of Science][Medline]
Hess, K.R., Wong, E.T., Jaeckle, K.A., Kyritsis, A.P., Levin, V.A., Prados, M.D., and yung, W.K. (1999) Response and progression in recurrent malignant glioma. Neuro-Oncology 1, 282-288.[Abstract]
Kaplan, E.L., and Meier, P. (1958) Non-parametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457-481.[CrossRef][Web of Science]
Lang, F.F., Gilbert, M.R., Puduvalli, V.K., Weinberg, J., Levin, V.A., yung, W.K., Sawaya, R., Fuller, G.N., and Conrad, C.A. (2002) Toward better early-phase brain tumor clinical trials: A reappraisal of current methods and proposals for future strategies. Neuro-Oncology 4, 268-277.[Abstract]
Levitt, R., Buckner, J.C., Cascino, T.L., Burch, P.A., Morton, R.F., Westberg, M.W., Goldberg, R.M., Gallagher, J.G., O'Fallon, J.R., and Scheithauer, B.W. (1995) Phase II study of amonafide in patients with recurrent glioma. J. Neurooncol. 23, 87-93.[CrossRef][Medline]
Mick, R., Crowley, J.J., and Carroll, R.J. (2000) Phase II clinical trial design for noncytotoxic anticancer agents for which time to disease progression is the primary endpoint. Control. Clin. Trials 21, 343-359.[CrossRef][Web of Science][Medline]
Moynihan, T.J., O'Fallon, J.R., Krook, J.E., Schomberg, P., Dinapoli, R.P., Kazem, I., Scheithauer, B., and Buckner, J.C. (2002) A phase II trial of pre-irradiation chemotherapy with BCNU, cisplatin and oral etoposide combined with radiation therapy in the treatment of glioblastoma (GBM). Proc. Am. Soc. Clin. Oncol. 21, 77a (abstract 306).
Peto, R., and Peto, J. (1972) Asymptotically efficient rank invariant procedures (with discussion). J. R. Stat. Soc. [A] 135, 185-207.[CrossRef]
Rajkumar, S.V., Buckner, J.C., Schomberg, P.J., Cascino, T.L., Burch, P.A., and Dinapoli, R.P. (1998a) Phase I evaluation of radiation combined with recombinant interferon alpha-2a and BCNU for patients with high-grade glioma. Int. J. Radiat. Oncol. Biol. Phys. 40, 297-302.[CrossRef][Web of Science][Medline]
Rajkumar, S.V., Buckner, J.C., Schomberg, P.J., Pitot IV, H.C., Ingle, J.N., and Cascino, T.L. (1999a) Phase I evaluation of preirradiation chemotherapy with carmustine and cisplatin and accelerated radiation therapy in patients with high-grade gliomas. Neurosurgery 44, 67-73.[CrossRef][Web of Science][Medline]
Rajkumar, S.V., Buckner, J.C., Schomberg, P.J., Reid, J.M., Bagniewski, P.J., Ames, M.M., Cascino, T.L., and Marks, R.S. (1998b) Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma. Int. J. Radiat. Oncol. Biol. Phys. 42, 969-975.[CrossRef][Web of Science][Medline]
Rajkumar, S.V., Burch, P.A., Nair, S., Dinapoli, R.P., Scheithauer, B., O'Fallon, J.R., Etzell, P.S., Leitch, J.M., Morton, R.F., and Marks, R.S. (1999b) Phase II North Central Cancer Treatment Group study of 2-chlorodeoxyadenosine in patients with recurrent glioma. Am. J. Clin. Oncol. 22, 168-171.[CrossRef][Web of Science][Medline]
Rajkumar, S.V., Reid, J.M., Novotny, P.J., Safgren, S.L., Scheithauer, B.W., Johnson, P.S., Nair, S., Morton, R.F., Hatfield, A.K., Krook, J.E., Ames, M.M., and Buckner, J.C., for the North Central Cancer Treatment Group (2000) A randomized phase II and pharmacokinetic study of dacarbazine in patients with recurrent glioma. J. Neurooncol. 49, 255-261.[CrossRef][Medline]
Rao, R.D., Thome, S.D., O'Fallon, J., Earle, J.D., Dinapoli, R.P., and Buckner, J.C. (2002) Safety of thrice-daily hyperfractionated radiation and BCNU for high-grade gliomas. Int. J. Radiat. Oncol. Biol. Phys. 53, 376-384.[CrossRef][Web of Science][Medline]
Reid, J.M., Buckner, J.C., Schaaf, L., Cha, S., Wright, K., Marks, R., Wiesenfeld, M., Pfeifle, D., Hatfield, A., Krook, J., Duncan, B., and Miller, L. (2000) Anticonvulsants alter the pharmacokinetics of irinotecan (CPT-11) in patients with recurrent glioma. Proc. Am. Soc. Clin. Oncol. 19, 160a (abstract 620).
Sargent, D.J., Wieand, H.S., Haller, D.G., Gray, R., Benedetti, J.K., Buyse, M., Labianca, R., Seitz, J.F., O'Callaghan, C.J., Francini, G., Grothey, A., O'Connell, M., Catalano, P.J., Blanke, C.D., Kerr, D., Green, E., Wolmark, N., Andre, T., Goldberg, R.M., and De Gramont, A. (2005) Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials. J. Clin. Oncol. 23, 8664-8670.
Sekine, I., Tamura, T., Kunitoh, H., Kubota, K., Shinkai, T., Kamiya, y., and Saijo, N. (1999) Progressive disease rate as a surrogate endpoint of phase II trials for non-small-cell lung cancer. Ann. Oncol. 10, 731-733.
Simon, R. (1989) Optimal two-stage designs for phase II clinical trials. Control. Clin. Trials 10, 1-10.[Medline]
Uhm, J.H., Ballman, K.V., Giannini, C., Krauss, J.C., Buckner, J.C., James, D., Scheithauer, B.W., O'Fallon, J.R., and Jaeckle, K.A. (2004) Phase II study of ZD1839 in patients with newly diagnosed grade 4 astrocytoma. J. Clin. Oncol. 22(suppl.), 108s (abstract 1505).
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