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© 2003 American Society for Clinical Oncology RSR13 Plus Cranial Radiation Therapy in Patients With Brain Metastases: Comparison With the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database
From the Wake Forest University School of Medicine, Winston-Salem, NC; Cleveland Clinic Foundation, Cleveland, OH; St Vincent’s Hospital, Worcester, MA; University of Arizona Health Sciences Center, Tucson, AZ; and Radiation Therapy Oncology Group, Philadelphia, PA. Address reprint requests to Edward G. Shaw, MD, Department of Radiation Oncology, Wake Forest University (WFU) School of Medicine and the Comprehensive Cancer Center of WFU at the WFU Baptist Medical Center, Medical Center Blvd, Winston-Salem, NC 27157-1030; email: eshaw{at}wfubmc.edu.
Purpose: This phase II, open-label, multicenter study assessed the efficacy and safety of the potential radiation enhancer RSR13 plus cranial radiation therapy (RT) in patients with brain metastases. The primary end point was patient survival in comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). Patients and Methods: Eligibility criteria were age ≥ 18 years, Karnofsky performance score ≥ 70, and brain metastases with solid tumor histology. Patients received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 50 to 100 mg/kg intravenously over 30 minutes. Univariate and multivariate comparisons of survival and cause of death were made between class II study patients and RTOG BMD patients. Results: Fifty-seven RPA class II patients were enrolled. With a minimum follow-up of 24 months, the median survival time and 1- and 2-year survival rates were 6.4 months, 23%, and 11% for the RSR13-treated patients compared with 4.1 months, 15%, and 3% for the RTOG BMD patients (P = .0174). In an exact-matched case analysis (n = 38), median survival time for RSR13 patients was 7.3 months versus 3.4 months for the RTOG BMD patients (P = .006). There was a 54% reduction in the risk of death for RSR13 patients (P = .0267). RSR13-related adverse events of greater than or equal to grade 3 toxicity that occurred in more than one patient included hypoxia, headache, anemia, fatigue, hypertension, and intracranial hypertension. Conclusion: RSR13 plus cranial RT resulted in a significant improvement in survival, as well as a reduction in death due to brain metastases, compared with class II patients in the RTOG BMD.
IN THE United States alone, between 80,000 and 170,000 individuals develop brain metastases each year.1,2 Standard palliative treatment for multiple symptomatic lesions consists of corticosteroids and cranial (ie, whole-brain [WB]) radiation therapy (RT), which will relieve symptoms and temporarily improve neurologic function in a majority of patients.2,3 However, analysis of a large database compiled by the Radiation Therapy Oncology Group (RTOG) indicates that the overall prognosis for patients with brain metastases remains poor, with a median survival time (MST) of approximately 4 to 7 months even in subgroups with more favorable clinical features.4 Even in patients with a solitary metastasis or 2 to 4 metastases, local control after WBRT was 0% to 47%.5,6 The likelihood of achieving a complete response ranges from 0% to 24% in patients with radioresistant tumors such as melanoma and renal cell cancer.7 Hypoxic tumor cells are more resistant to DNA damage by ionizing radiation than oxic cells.8 Tumor hypoxia also adversely affects the clinical outcome (ie, local control, survival) of irradiated solid tumors.9–12 Oxygen measurements in human tumors have confirmed tumor hypoxia in glioblastoma multiforme,13 brain metastases,13,14 squamous cell carcinomas of the uterine cervix,15 and head and neck16 and breast carcinomas.17 Several clinical studies have demonstrated that tumors with a low median partial pressure of oxygen (pO2) have a higher in-field failure rate after RT. When compared with well-oxygenated tumors of similar size and state, patients with tumors of the uterine cervix have been found to have an increased recurrence rate if the median pO2 is less than 10 mmHg.15 This has also been observed in head and neck cancer.16 Based on these data, even a small hypoxic fraction in a tumor may affect the probability that some tumor cells will survive a given dose of radiation. RSR13 is a synthetic allosteric modifier of hemoglobin, the first of a new class of pharmaceutical agents. RSR13 is a small molecule that noncovalently binds in the central water cavity of the hemoglobin tetramer and decreases hemoglobin-oxygen binding affinity,18 described by an increase in p50 (ie, the pO2 that results in 50% hemoglobin saturation). By this action, RSR13 facilitates the release of oxygen from hemoglobin and increases tissue pO2.19–21 In animal studies, RSR13 enhanced the effect of radiation on tumors, an effect demonstrated to be oxygen-dependent,19 with no direct cytotoxic effect on tumor, bone marrow, or skin.19,22 Unlike prior radiation sensitizers, the radiation-enhancing effect of RSR13 is not dependent on its diffusion into the tumor tissue, but on an increase in tumor pO2. The fact that RSR13 does not have to enter the cancer cell to increase radiation sensitivity is especially important in both primary and metastatic brain tumors, in which the blood-brain barrier acts to exclude or impede the entry of chemical agents into the brain parenchyma. The present study was undertaken to determine whether RSR13, given with standard cranial RT, could improve survival, response rate, and local control in patients with brain metastases. As specified in the protocol, study results were compared with data from the RTOG Recursive Partitioning Analysis Brain Metastases Database (RPA BMD), initially described by Gaspar et al4 in 1997 and further validated by Gaspar et al23 in 2000.
Patient Enrollment and Eligibility Between February 1998 and May 1999, 17 sites enrolled patients with brain metastases onto the study protocol. Patients were stratified on enrollment into RTOG RPA class I or II (Fig 1  ) because of the different expected survival between classes (MSTs of 7.1 and 4.2 months for classes I and II, respectively). Separate sample size calculations were performed by stratum: planned enrollment was 54 RPA class I and 50 RPA class II patients to reach 51 and 48 assessable patients, respectively. Study enrollment was closed after the class II enrollment target was met; at that time, only 12 class I patients had been enrolled. Enrollment of RPA class I patients proceeded slowly because of the smaller proportion of class I patients (20%) compared with class II patients (65%) in the overall population of patients with brain metastases.4 In addition, potential class I participants often received surgery, stereotactic radiosurgery, or a different RT regimen, all of which precluded their participation. Because of the small sample size of class I patients, data from these patients were not included in the RTOG BMD comparison. However, data from class I and class II patients were combined for the safety and toxicity analyses.
Potential study participants were identified and screened for eligibility. Any male or nonpregnant female patient with breast, non–small-cell lung (NSCL), melanoma, genitourinary (GU), or gastrointestinal (GI) primary cancer and brain metastases was eligible for enrollment if he or she met the following criteria: Age of at least 18 years; histologically or cytologically confirmed brain metastases, or radiographic studies consistent with brain metastases and histologically or cytologically confirmed breast, NSCL, melanoma, GU, or GI primary cancer (if no obvious primary cancer was seen, then a histological diagnosis consistent with a breast, NSCL, melanoma, GU, or GI primary cancer was sufficient for entry); a Karnofsky performance score (KPS) ≥ 70; fulfillment of the RTOG criteria for RPA class I or class II; no prior treatment for brain metastases (except corticosteroid therapy); no chemotherapy within 1 week before the start of RT or during RSR13 plus RT administration; weight ≤ 120 kg; baseline resting arterial oxygen saturation (SpO2) on room air ≥ 90% by pulse oximetry; adequate hematologic, hepatic, and renal function; no known history of hemoglobinopathy; if the patient had a pulmonary condition that compromised oxygen loading in the lungs, satisfactory performance on a pulmonary function test and fulfillment of exercise SpO2 requirements; no other serious intercurrent medical illness or active malignancy from a second histological site; no prior use of RSR13; no use of any investigational drug, biologic, or device within 3 weeks before study start; and ability to provide written informed consent. The protocol was approved by the institutional review boards of all participating institutions, and written informed consent was obtained from all patients before entry onto the study.
RSR13 Plus RT Treatment
End Points and Evaluations Survival time was defined as the period from the first day of RT (RT day 1) to death. Progression-free survival was calculated from RT day 1 to documented disease progression or death, and the time to tumor progression was the period from RT day 1 to documented disease progression. The investigators’ determinations of tumor response and disease progression were used in the data analysis. The following criteria defined tumor response and disease progression. For patients with more than one lesion in the brain, all lesions must have demonstrated a decrease in size with a stable or decreasing steroid dose to meet the criteria for CR or PR. CR was defined as a disappearance of all brain lesions seen on computed tomography (CT) or magnetic resonance imaging (MRI) scans for at least 1 month with stable or decreasing steroid dose. PR required at least a 50% decrease in all lesions for at least 1 month with a stable or decreasing steroid dose. Stable disease was defined as any lesion with shrinkage less than 50% or growth less than 25% (included all lesions with no change in growth). Disease progression was defined as any lesion in the brain enlarged by more than 25% with a stable or increased steroid dose, any new lesion, or clinical deterioration with a stable scan image. An "other" response category included patients with progressive disease, patients without a follow-up CT scan, or patients who withdrew from the study or died before the 1-month follow-up visit and who were usually not evaluated for response by MRI or CT scan. For measurable disease, standard biperpendicular diameters of the two-dimensional tumor image at maximum dimension were applied. Statistical analyses were conducted independently by a member of the RTOG statistics group (C.S.) and the corporate sponsor’s statistician (J.H.). For all statistical analyses, P values were two-sided and P < .05 was considered statistically significant. All patients in this analysis were observed for survival until death or for a minimum of 24 months. The final date for inclusion of survival data was July 23, 2001. Survival was estimated using the Kaplan-Meier method. Comparison of survival data from the RSR13 study versus survival data from class II patients in the RTOG BMD was conducted using the log-rank test. Exact-matched cases were obtained by case matching class II patients in the RSR13 study to patients in the RTOG BMD by KPS, primary tumor site, extent of metastases, status of primary tumor, and age (within 5 years). Cases were matched only once and resampling was not performed. The Kaplan-Meier estimates were performed once a data set was obtained and log-rank tests were conducted. Survival data were also analyzed using a multivariable Cox proportional hazards regression model with baseline characteristics and study group as factors. Covariates were included in the model in a stepwise fashion. A stratified Cox model, with each matched pair (RTOG BMD:RSR13) as a stratum and the study group as the only independent factor, was also used to estimate RSR13 treatment effect. Cause of death was based on participating institutions’ reports and was compared for study patients versus the RTOG BMD patients. The Fisher’s exact test was used to compare the cause of death as brain metastases versus all other causes.
Safety Adverse events and toxicities were assessed by the frequency of treatment emergent events and categorized according to preferred terms of the World Health Organization Adverse Reaction Thesaurus. All adverse events were graded by the investigators with regard to relationship to study treatment (definitely, probably, possibly, or not related) and severity (mild = grade 1, moderate = grade 2, and severe = grades 3 and 4). Investigators graded toxicities in the radiation portal using the RTOG Acute Radiation Morbidity Scoring Criteria, and those outside of the radiation portal using Division of Cancer Treatment and Diagnosis/National Cancer Institute Common Toxicity Criteria. Adverse events that could not be graded by either toxicity criteria were classified by severity. Serious adverse events were defined as those events that met any of the following criteria: the event was fatal, was life-threatening, resulted in persistent or significant disability/incapacity, required inpatient hospitalization or prolongation of existing hospitalization, was a congenital anomaly/birth defect, or was an important medical event.
Patient Characteristics A total of 69 patients with brain metastases were enrolled, including 12 and 57 RPA class I and II patients, respectively. Due to the small sample size of class I patients, only data from class II patients are presented in the survival analyses, although class I patients are included in the safety and toxicity analysis.
Characteristics of the RTOG BMD patients and the class II patients in the RSR13 study are summarized in Table 1
Survival The 57 RPA class II patients with brain metastases in the intent-to-treat analysis for MST were observed until death or for a minimum of 24 months. Three patients were living at the time of the analysis.
Survival results are presented in Tables 2
Using the exact-matched RTOG BMD controls (n = 38), the difference in survival was even more significant (P = .0060) than the overall comparison, with MST at 7.3 months (95% CI, 4.6 to 10.9 months) versus 3.4 months (95% CI, 1.7 to 5.0 months). Survival rates for the exact-match cases at 6 months, 1 year, and 2 years were 58%, 24%, and 13%, respectively, for patients treated with RSR13 versus 21%, 8%, and 3%, respectively, for the RTOG BMD patients.
RSR13 Treatment Effect on Risk of Death
Analysis of Covariates
Cause of Death Fifty-four of the 57 class II patients in the RSR13 study died, and there was a minimum of 24 months of follow-up on the 3 patients who were still living. Of these 54 patients, seven (13%) were known to have died primarily as a result of their brain metastases. By comparison, in the RTOG BMD, 111 (37%) of 298 patients died as a result of their brain metastases (P = .0003). Systemic cancer was the primary cause of death for 28 (52%) of the 54 RSR13 study patients and 120 (40%) of the 298 RTOG BMD patients. Causes of death for the 19 class II RSR13 patients whose deaths were not ascribed to primarily systemic cancer or brain metastases included the following: unable to distinguish (ie, could not differentiate brain v systemic death),6 unknown,6 and other (n = 7; ie, stroke, pneumonia, or sepsis).
Imaging-Based Response in the Brain
Adverse Effects Safety data for patients in RPA class I and class II have been combined (n = 69). Sixteen (23%) of the 69 enrolled patients withdrew from the study. Ten patients withdrew from the study during the RSR13 plus RT dosing phase: seven due to adverse events, one due to death, one for an unspecified reason, and one lost to follow-up. Six patients withdrew from the study after completing the RSR13 dosing phase: three due to death, two due to unsatisfactory response, and one due to noncompliance. Overall, 55 (80%) of 69 patients completed ≥ 90% of RSR13 doses and 60 (88%) of 69 patients completed ≥ 70% of RSR13 doses. The majority of patients (62%, 43 of 69 patients) received the full 100 mg/kg RSR13 dose. Dose reductions occurred in 21 (30%) of 69 patients due to toxicity and 5 (7%) of 69 patients for protocol exemptions. In most cases of dose reduction, patients received an RSR13 dose of 75 mg/kg. Only two patients had dose reductions to 50 mg/kg. All study patients experienced at least one adverse event. The most common all-causality adverse events, those events occurring in 25% or more of patients, included headache (49%, 34 of 69 patients), nausea (45%, 31 of 69 patients), fatigue (42%, 29 of 69 patients), hypoxia (41%, 28 of 69 patients), vomiting (38%, 26 of 69 patients), dizziness (32%, 22 of 69 patients), and alopecia (28%, 19 of 69 patients).
Adverse events that were considered possibly, probably, or definitely related to RSR13 and that occurred in 10% or more of total patients (n = 69) are summarized by toxicity grade in Table 5
Twenty-one of the 69 study patients (30%) experienced one or more serious adverse events. Ten patients (14%) experienced serious adverse events that were considered to be related to RSR13 treatment. The symptoms of the RSR13-related serious adverse events in these 10 patients included hypoxia, hypotension, postural hypotension, acute renal failure, abnormal renal function, nausea/vomiting, syncope, anemia, intracranial hypertension, convulsions, confusion, fever, and cognitive impairment. Clinically significant laboratory abnormalities were generally infrequent. Mean erythroid parameters (RBC count, hemoglobin concentration, and hematocrit) all showed decreases from baseline during treatment. Thus, mean hemoglobin concentration was 13.2 ± 1.4 g/dL at baseline, 11.8 ± 1.3 g/dL on RT day 10, and 12.6 ± 1.3 g/dL one month after the end of RSR13 plus RT. Mean WBC number decreased over time, but remained within the normal range during the study. Mean creatinine concentration was 0.75 ± 0.23 mg/dL at baseline, 0.83 ± 0.46 mg/dL on RT day 10, and 0.76 ± 0.27 mg/dL 1 month after the end of RSR13 plus RT. Increased blood creatinine was reported as an adverse event in three patients. These events were reported as moderate2 or severe,1 and were all considered as possibly2 or definitely1 related to RSR13.
Change in p50
Despite three decades of clinical trials, the outcome of patients with brain metastases has changed little. There have been a total of eight randomized trials looking at different dose-fractionation schedules for cranial RT alone, ranging from 10 Gy in 1 fraction to 30 Gy in 10 fractions to 50 Gy in 20 fractions. As indicated in Table 6 , survival has been around 4 months without an advantage of one dose-fractionation schedule over another. Even the addition of various potential radiation dose modifiers has made little difference. Randomized trials using lonidamine, misonidazole, bromodeoxyuridine, nimustine, fluorouracil/nimustine, and motefaxin gadolinium have all been negative (Table 7), even indicating an overall survival disadvantage for some sensitizer-treated patients.
In the present study, RSR13, an allosteric modifier of hemoglobin, was used to increase tumor oxygenation due to decreased hemoglobin-oxygen binding affinity. Unlike other radiation sensitizers, RSR13 does not have to penetrate into the tumor to function. Rather, it only needs to enhance pO2 in the tumor by facilitating the release of oxygen from hemoglobin. Using the class II RTOG BMD as a control, RSR13-treated patients were found to have an improved MST; improved 6-month, 1-year, and 2-year survival rates; and a reduction in death from brain metastases. One study patient with multiple bilateral brain metastases from melanoma had a reduction in the number and size of lesions after cranial RT plus RSR13 (Fig 4  ), including a CR of some lesions. In a study of imaging-based response to cranial RT of 300 Gy in 10 fractions, Nieder et al7 reported a 0% CR rate for metastatic melanoma. The same study also identified a poor CR rate for another radioresistant histology and renal cell cancer, as well as centrally necrotic (presumably hypoxic) metastases. All patients on the trial experienced at least one adverse event; 30% had one or more serious adverse events, but only 14% of patients experienced serious adverse events considered to be related to RSR13 treatment. Adverse events observed in the study patients resulted from the administration of cranial RT plus RSR13 and the patients’ underlying illnesses (mostly lung cancer associated with chronic obstructive pulmonary disease). Because of the RSR13 mechanism of action, some adverse events were expected. RSR13 decreases the hemoglobin-oxygen binding affinity and reduces oxygen loading in the lungs at ambient oxygen pressure. This PD effect is manifested by a transient reduction in SpO2 measured by standard cutaneous pulse oximetry. The vast majority of patients receiving RSR13 have predictable, dose-related, mild, and transient reductions in SpO2, ie, hypoxemia. This is why supplemental oxygen, 4 L/min by nasal cannula, is administered during and for a specified period after RSR13 administration. In this study, the overall incidence of hypoxemia was 41%, somewhat higher than the rates (31%) seen in studies of RSR13 in 136 patients with primary brain cancer.36 Only the first study conducted for this indication has been published. The higher incidence of hypoxemia in patients with brain metastases was likely due to the high proportion (58%) of enrolled patients who had primary lung cancer or lung metastases. Because the magnitude of the PD effect is related to RSR13 dose, withholding or reducing doses were used to manage hypoxemia-associated adverse events. In July 2002, Allos Therapeutics, Inc completed a 538-patient phase III randomized trial of standard cranial RT (300 Gy in 10 fractions) plus supplemental oxygen versus standard cranial RT plus supplemental oxygen along with 10 doses of preirradiation RSR13 (dose and schedule comparable to the phase II trial reported herein). The impetus for this phase III trial was the improvements in MST and 6-month, 1-year, and 2-year survival rates, and in the reduction in death as a result of brain metastases, reported in the present study.
Supported by grant nos. RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA 32115 from the National Cancer Institute. The Wake Forest University School of Medicine’s General Clinical Research Center is supported by National Institutes of Health grant no. M01-RR07122. M.G. was sponsored by Allos Therapeutics, Inc, Westminster, CO. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute.
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36. Kleinberg L, Grossman SA, Piantadosi S, et al: Phase I trial to determine the safety, pharmacodynamics, and pharmacokinetics of RSR13, a novel radioenhancer, in newly diagnosed glioblastoma multiforme. J Clin Oncol 17:2593–2603, 1999 Submitted August 19, 2002; accepted March 24, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
