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Improving the Efficiency of Clinical Trials Through Selection Models
Volume 84 Number 3S Supplement 2012 contribute to high industry involvement. The impact of industry funding versus institutional or governmental sources of funding for cancer research is unclear, and requires further study. Author Disclosure: S. Lloyd: None. D. Buscariollo: None. C.P. Gross: None. D.V. Makarov: None. J.B. Yu: None.
112 Improving the Efficiency of Clinical Trials Through Selection Models K. Zakeri,1 B.S. Rose,2 and L.K. Mell1; 1University of California, San Diego, La Jolla, CA, 2Harvard University, Boston, MA Purpose/Objective(s): Clinical trial efficiency may be improved using selection models to identify patients with favorable risk profiles for the events of interest. However, selection decreases a trial’s accrual rate, with uncertain impact on overall cost. Materials/Methods: We modeled cost (C) as a function of time (t), as: C(t) Z Cs+Cmt+bCas+bCf(lsee-lt(else1))/ l2, where Cs is the startup cost, Cm is the fixed cost per year, t is the trial duration in years, b is the accrual rate, Ca is the cost per individual of accrual, s is the length of accrual in years, Cf is the cost per patient-year of follow-up, and l is the event hazard. The model assumes linear accrual and exponential hazards, allows for differing survival in each treatment arm, and penalizes longer accrual with fixed annual costs. Inputs to the cost model were based on data from the Institute of Medicine Report for oncology clinical trials and included Cs of $20,000 and Cm of $20,000 with a range of inputs for Ca of $3,000-$9,000 and for Cf of $100-$300. We apply the cost function to data from the SWOG 8794 randomized trial of adjuvant radiation therapy in 425 highrisk prostate cancer patients following radical prostatectomy. We used previously-developed risk models to identify an enriched subgroup of 188 patients (44%) at high risk for metastasis and low risk for competing mortality, based on risk scores. We estimated the cost differences for a clinical trial with a primary endpoint of metastasis-free survival (MFS) (i.e., time to metastasis or death) in the whole cohort versus subsample, assuming an accrual rate proportional to the size of the subsample. Power calculations assumed type I and II error of 0.10 and 0.20, and accrual and follow-up times of 6 and 6 years, respectively. Results: The 10-year incidences of metastasis in the enriched subgroup versus whole cohort were 33% (95% CI, 23-43%) versus 20% (95% CI, 15-26%), respectively. The 10-year incidences of competing mortality in the subgroup versus whole cohort were 14% (95% CI, 8-23%) versus 20% (95% CI, 15-26%), respectively. The estimated cost of the trial ranged from 50-53% less in the subgroup compared to the whole cohort ($1,280,000-$3,320,000 vs. $2,550,000-$7,130,000, respectively), while the estimated trial length was similar (12.1 vs. 12 years, respectively). Conclusions: The use of selection models in clinical trial design can potentially result in large cost savings. Author Disclosure: K. Zakeri: None. B.S. Rose: None. L.K. Mell: None.
113 Radiation Intensification in the Context of Concurrent Chemotherapy: Fruitful or Futile? A 20-year Meta-analysis of Phase III Randomized Controlled Trials Across Different Disease Sites K. Yamoah, T. Showalter, and N. Ohri; Thomas Jefferson University Hospital, Philadelphia, PA Purpose/Objective(s): Many trials have studied the effect of radiation dose intensification on disease control with mixed results however, the benefit of dose escalation in patients receiving chemotherapy as part of their treatment regimen remains unclear. In this meta-analysis we attempt to determine whether the paradigm of radiation therapy intensification has been successful, particularly in the context of concurrent chemotherapy. Materials/Methods: The PUBMED and Cochrane Library databases were systematically searched to identify randomized, controlled studies on radiation dose escalation trials with or without chemotherapy from January 1993 to January 2012. Our search included trials testing intensification of radiation therapy (RT) using dose escalation and/or altered fractionation
Oral Scientific Sessions
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schedules. Endpoints included local control (LC) and overall survival (OS). Endpoints from trials reporting on biochemical control, local recurrence or loco-regional control were collectively analyzed as Local Control. Hazard ratios (HR) describing the impact of RT intensification on OS and LC were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p < 0.10 using Q test). Results: A total of 17,760 patients from 29 trials on eight disease sites comprising the CNS, Head and Neck, Breast, Prostate, Cervix, Gastrointestinal, Lung and Brain met study criteria for selection. 26 trials had information on OS whereas 22 trials had information on LC. 7 trials studied RT intensification with concurrent chemotherapy. Using random effects models, RT intensification was associated with a benefit in LC (HR Z 0.76, 95% CI 0.69-0.84; p Z 0.0001) and a trend towards benefit in OS (HR Z 0.95, 95% CI 0.89-1.00; p Z 0.053). In a subgroup analysis of trials that did not use concurrent chemotherapy there was a significant benefit in both LC and OS; (HR Z 0.74, 95% CI 0.67-0.81; p < 0.0001) and (HR Z 0.93, 95% CI 0.87-0.99; p Z 0.02) respectively. We observed no statistically significant benefit in either LC or OS endpoints in trials that employed RT intensification in the context of concurrent chemotherapy (HR Z 1.01, 95% CI 0.96-1.05; p Z 0.08) and (HR Z 1.08, 95% CI 0.871.34; p Z 0.5) respectively. Conclusions: Clinical trials testing intensification of RT without chemotherapy have had favorable results. Similar trials incorporating concurrent chemotherapy have not shown benefit to radiation therapy intensification. Further studies aimed at understanding the radiobiology of tumor response to irradiation in the context of concurrent chemotherapy are required in order to appropriately design future dose escalation trials. Author Disclosure: K. Yamoah: None. T. Showalter: None. N. Ohri: None.
114 Retrospective Cohort Analysis of Risk of First and Recurrent Stroke in Childhood Cancer Survivors Treated With Cranial Radiation Therapy S. Mueller,1 K. Sear,1 N. Hills,1 N. Chettout,1 S. Afghani,2 L. Keiko,1 E. Tolentino,1 D. Haas-Kogan,1 and H. Fullerton1; 1University of California, San Francisco, San Francisco, CA, 2University of California, Berkeley, San Francisco, CA Purpose/Objective(s): Treatment with cranial radiation therapy (CRT) increases the risk of stroke in survivors of pediatric cancer. In this current investigation we assessed rates and predictors of first and recurrent stroke in childhood cancer survivors treated with CRT. Materials/Methods: We performed chart abstraction (n Z 384) and phone interviews (n Z 104) to measure first and recurrent stroke in children who received CRT at a single institution, 1980-2009. Incidence of first-stroke was calculated as the number of first strokes per person-years of observation after radiation. We used survival analysis techniques to determine the cumulative incidence of first stroke after radiation, and recurrent stroke after first stroke; we used Cox proportional hazards models to examine potential predictors of first stroke. Results: Median age of children at the time of CRT treatment was 8 years (IQR 4-13) with a median age at last follow-up of 21.1 years (range Z 3.647.3 years). The bulk of patients were alive (n Z 274; 71.4%) and only five patients reported a history of Neurofibromatosis 1 (NF1). The majority of children carried a diagnosis of a brain tumor (57.5%), followed by retinoblastoma (10%) and acute lymphoblastic leukemia (3%). A total of 19 first-strokes (11 ischemic, 4 hemorrhagic, 4 unknown sub-type) were identified at a median age of 24 years (IQR 17-33 years): 6 from chart review, 10 from interview, and 3 from both. Presenting stroke symptoms included hemiparesis (n Z 12), hemi-sensory loss (n Z 9), dysarthria (n Z 8), difficulty walking (n Z 6), headache (n Z 7), seizure (n Z 2), vertigo (n Z 2), and altered mental status (n Z 1). Imaging was available in 12 cases and consistent with stroke in all. Five patients had evidence of vasculopathy on imaging. The overall rate of first-stroke was 625 (95% CI 577-676) per 100,000 person-years. Median time to develop a first stroke
112 Improving the Efficiency of Clinical Trials Through Selection Models K. Zakeri,1 B.S. Rose,2 and L.K. Mell1; 1University of California, San Diego, La Jolla, CA, 2Harvard University, Boston, MA Purpose/Objective(s): Clinical trial efficiency may be improved using selection models to identify patients with favorable risk profiles for the events of interest. However, selection decreases a trial’s accrual rate, with uncertain impact on overall cost. Materials/Methods: We modeled cost (C) as a function of time (t), as: C(t) Z Cs+Cmt+bCas+bCf(lsee-lt(else1))/ l2, where Cs is the startup cost, Cm is the fixed cost per year, t is the trial duration in years, b is the accrual rate, Ca is the cost per individual of accrual, s is the length of accrual in years, Cf is the cost per patient-year of follow-up, and l is the event hazard. The model assumes linear accrual and exponential hazards, allows for differing survival in each treatment arm, and penalizes longer accrual with fixed annual costs. Inputs to the cost model were based on data from the Institute of Medicine Report for oncology clinical trials and included Cs of $20,000 and Cm of $20,000 with a range of inputs for Ca of $3,000-$9,000 and for Cf of $100-$300. We apply the cost function to data from the SWOG 8794 randomized trial of adjuvant radiation therapy in 425 highrisk prostate cancer patients following radical prostatectomy. We used previously-developed risk models to identify an enriched subgroup of 188 patients (44%) at high risk for metastasis and low risk for competing mortality, based on risk scores. We estimated the cost differences for a clinical trial with a primary endpoint of metastasis-free survival (MFS) (i.e., time to metastasis or death) in the whole cohort versus subsample, assuming an accrual rate proportional to the size of the subsample. Power calculations assumed type I and II error of 0.10 and 0.20, and accrual and follow-up times of 6 and 6 years, respectively. Results: The 10-year incidences of metastasis in the enriched subgroup versus whole cohort were 33% (95% CI, 23-43%) versus 20% (95% CI, 15-26%), respectively. The 10-year incidences of competing mortality in the subgroup versus whole cohort were 14% (95% CI, 8-23%) versus 20% (95% CI, 15-26%), respectively. The estimated cost of the trial ranged from 50-53% less in the subgroup compared to the whole cohort ($1,280,000-$3,320,000 vs. $2,550,000-$7,130,000, respectively), while the estimated trial length was similar (12.1 vs. 12 years, respectively). Conclusions: The use of selection models in clinical trial design can potentially result in large cost savings. Author Disclosure: K. Zakeri: None. B.S. Rose: None. L.K. Mell: None.
113 Radiation Intensification in the Context of Concurrent Chemotherapy: Fruitful or Futile? A 20-year Meta-analysis of Phase III Randomized Controlled Trials Across Different Disease Sites K. Yamoah, T. Showalter, and N. Ohri; Thomas Jefferson University Hospital, Philadelphia, PA Purpose/Objective(s): Many trials have studied the effect of radiation dose intensification on disease control with mixed results however, the benefit of dose escalation in patients receiving chemotherapy as part of their treatment regimen remains unclear. In this meta-analysis we attempt to determine whether the paradigm of radiation therapy intensification has been successful, particularly in the context of concurrent chemotherapy. Materials/Methods: The PUBMED and Cochrane Library databases were systematically searched to identify randomized, controlled studies on radiation dose escalation trials with or without chemotherapy from January 1993 to January 2012. Our search included trials testing intensification of radiation therapy (RT) using dose escalation and/or altered fractionation
Oral Scientific Sessions
S45
schedules. Endpoints included local control (LC) and overall survival (OS). Endpoints from trials reporting on biochemical control, local recurrence or loco-regional control were collectively analyzed as Local Control. Hazard ratios (HR) describing the impact of RT intensification on OS and LC were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p < 0.10 using Q test). Results: A total of 17,760 patients from 29 trials on eight disease sites comprising the CNS, Head and Neck, Breast, Prostate, Cervix, Gastrointestinal, Lung and Brain met study criteria for selection. 26 trials had information on OS whereas 22 trials had information on LC. 7 trials studied RT intensification with concurrent chemotherapy. Using random effects models, RT intensification was associated with a benefit in LC (HR Z 0.76, 95% CI 0.69-0.84; p Z 0.0001) and a trend towards benefit in OS (HR Z 0.95, 95% CI 0.89-1.00; p Z 0.053). In a subgroup analysis of trials that did not use concurrent chemotherapy there was a significant benefit in both LC and OS; (HR Z 0.74, 95% CI 0.67-0.81; p < 0.0001) and (HR Z 0.93, 95% CI 0.87-0.99; p Z 0.02) respectively. We observed no statistically significant benefit in either LC or OS endpoints in trials that employed RT intensification in the context of concurrent chemotherapy (HR Z 1.01, 95% CI 0.96-1.05; p Z 0.08) and (HR Z 1.08, 95% CI 0.871.34; p Z 0.5) respectively. Conclusions: Clinical trials testing intensification of RT without chemotherapy have had favorable results. Similar trials incorporating concurrent chemotherapy have not shown benefit to radiation therapy intensification. Further studies aimed at understanding the radiobiology of tumor response to irradiation in the context of concurrent chemotherapy are required in order to appropriately design future dose escalation trials. Author Disclosure: K. Yamoah: None. T. Showalter: None. N. Ohri: None.
114 Retrospective Cohort Analysis of Risk of First and Recurrent Stroke in Childhood Cancer Survivors Treated With Cranial Radiation Therapy S. Mueller,1 K. Sear,1 N. Hills,1 N. Chettout,1 S. Afghani,2 L. Keiko,1 E. Tolentino,1 D. Haas-Kogan,1 and H. Fullerton1; 1University of California, San Francisco, San Francisco, CA, 2University of California, Berkeley, San Francisco, CA Purpose/Objective(s): Treatment with cranial radiation therapy (CRT) increases the risk of stroke in survivors of pediatric cancer. In this current investigation we assessed rates and predictors of first and recurrent stroke in childhood cancer survivors treated with CRT. Materials/Methods: We performed chart abstraction (n Z 384) and phone interviews (n Z 104) to measure first and recurrent stroke in children who received CRT at a single institution, 1980-2009. Incidence of first-stroke was calculated as the number of first strokes per person-years of observation after radiation. We used survival analysis techniques to determine the cumulative incidence of first stroke after radiation, and recurrent stroke after first stroke; we used Cox proportional hazards models to examine potential predictors of first stroke. Results: Median age of children at the time of CRT treatment was 8 years (IQR 4-13) with a median age at last follow-up of 21.1 years (range Z 3.647.3 years). The bulk of patients were alive (n Z 274; 71.4%) and only five patients reported a history of Neurofibromatosis 1 (NF1). The majority of children carried a diagnosis of a brain tumor (57.5%), followed by retinoblastoma (10%) and acute lymphoblastic leukemia (3%). A total of 19 first-strokes (11 ischemic, 4 hemorrhagic, 4 unknown sub-type) were identified at a median age of 24 years (IQR 17-33 years): 6 from chart review, 10 from interview, and 3 from both. Presenting stroke symptoms included hemiparesis (n Z 12), hemi-sensory loss (n Z 9), dysarthria (n Z 8), difficulty walking (n Z 6), headache (n Z 7), seizure (n Z 2), vertigo (n Z 2), and altered mental status (n Z 1). Imaging was available in 12 cases and consistent with stroke in all. Five patients had evidence of vasculopathy on imaging. The overall rate of first-stroke was 625 (95% CI 577-676) per 100,000 person-years. Median time to develop a first stroke