Phase II Multicenter Study of Induction Chemotherapy Followed by Concurrent Efaproxiral (RSR13) and Thoracic Radiotherapy for Patients With
http://www.100md.com
《临床肿瘤学》
the Vanderbilt University Medical Center, Nashville, TN
Centre H?spitalier Universitaire de Sherbrooke, Sherbrooke
H?pital Notre Dame
Montreal General Hospital
Jewish General Hospital, Montreal, Québec
Cross Cancer Institute, Edmonton
Tom Baker Cancer Centre, Calgary, Alberta, Canada
University of Arizona Health Sciences Center, Tucson, AZ
Radiation Therapy Oncology Group
Thomas Jefferson University, Philadelphia, PA
Johns Hopkins Hospital, Baltimore, MD
Tower Hematology/Oncology, Los Angeles, CA
University of Louisville, Louisville, KY
Allos Therapeutics Inc, Westminster, CO
ABSTRACT
PURPOSE: Efaproxiral (RSR13) reduces hemoglobin oxygen–binding affinity, facilitates oxygen release, and increases tissue pO2. We conducted a phase II multicenter study that assessed the efficacy and safety of efaproxiral when administered with thoracic radiation therapy (TRT), following induction chemotherapy, for treatment of locally advanced non–small-cell lung cancer (NSCLC).
PATIENTS AND METHODS: Fifty-one patients with locally advanced NSCLC were enrolled at 13 sites. Treatment comprised two cycles of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6), 3 weeks apart, followed by TRT (64 Gy/32 fractions) with concurrent efaproxiral (50 to 100 mg/kg). Survival results were compared with results of study Radiation Therapy Oncology Group (RTOG) 94-10.
RESULTS: Overall response rate was 75% (37 of 49 patients). Complete and partial response rates were 6% (three of 49 patients) and 69% (34 of 49 patients), respectively. Median survival time (MST) was 20.6 months (95% CI, 14.0 to 24.2); overall survival rates at 1- and 2-years were 67% and 37%, respectively. Survival results were compared with the sequential (S-CRT) and concurrent (C-CRT) chemoradiotherapy arms of RTOG 94-10. MSTs for cases matched by stage, Karnofsky performance status, and age were: RT-010, 20.6 months; S-CRT, 15.1 months; and C-CRT, 17.9 months. Grade 3 to 4 toxicities related to efaproxiral that occurred in more than one patient included transient hypoxemia (19%), radiation pneumonitis (11%), and fatigue (4%).
CONCLUSION: Addition of efaproxiral to S-CRT represents a promising approach in NSCLC treatment, and a randomized study should be pursued. The low incidence of grade 3 to 4 toxicities suggests that the use of efaproxiral instead of a cytotoxic agent, as a radiation sensitizer, may be advantageous.
INTRODUCTION
As the leading cause of cancer death in both men and women worldwide,[1] lung cancer requires innovative treatment regimens to improve treatment outcomes. Of all lung cancer cases, approximately 80% are non–small-cell lung cancer (NSCLC),[2] and 25% to 40% of NSCLC patients have stage III, locally advanced disease.[3] Most patients with stage III NSCLC are not candidates for surgical resection and are usually treated with a combination of chemotherapy and thoracic radiation therapy (TRT).[4] Despite such efforts, the majority of these patients relapse and die of their disease within 2 years of diagnosis.
For years, TRT alone was considered acceptable therapy for patients with locally advanced, unresectable stage III NSCLC. However, the therapy provided 5-year survival rates of only 5% to 7%, with a median survival time (MST) of 6 to 11 months.[5] In an attempt to improve these dismal survival results, the addition of full-dose induction chemotherapy administered before TRT was tested and shown to be superior to TRT alone.[5-7] The main objective of sequential chemoradiotherapy (S-CRT) was to improve patient outcome by reducing the risk of distant failure. Although S-CRT reduced the incidence of distant failure, there was no significant improvement in the rate of local control.[7] To improve local control, studies were also conducted in which lower dose chemotherapy was administered concurrently with TRT.[8-12] Concurrent chemoradiotherapy (C-CRT) was designed to maintain systemic control of distant disease while improving local control with the chemotherapy agent functioning as a radiation sensitizer. Randomized trials confirmed a reduction in the rate of local recurrence with C-CRT in comparison to S-CRT or TRT alone,[9,11] but there was no improvement in systemic control. Furthermore, patients treated with C-CRT experienced a higher incidence of grade 3 to 4 nonhematologic toxicities than patients treated with S-CRT.[10,13,14]
Hypoxic tumor cells are more resistant to radiation therapy (RT) than normal (oxic) cells,[15] and tumor hypoxia adversely affects the prognosis of patients receiving RT.[16-19] Oxygen measurements in human tumors have confirmed tumor hypoxia in glioblastoma multiforme (GBM),[20] brain metastases,[20,21] squamous cell carcinomas of the uterine cervix,[22] and head and neck[23] and breast carcinoma.[24] In lung tumors, an analysis conducted by Sasai et al[25] suggested an effect of hypoxia on tumor response to TRT, as arterial oxygen content was suggested to correlate with both local response and survival in NSCLC patients. Hemoglobin levels have also been shown to be statistically predictive indicators of survival in NSCLC patients, which may be related to a hypoxia effect on lung tumors.[26,27]
Efaproxiral (EFAPROXYN, RSR13) is a synthetic allosteric modifier of hemoglobin that noncovalently binds to the hemoglobin tetramer and decreases hemoglobin-oxygen binding affinity.[28] By this action, efaproxiral facilitates the release of oxygen from hemoglobin. Animal studies have demonstrated that efaproxiral increases tissue PO2[29,30] and oxygenation of tumors.[31] Efaproxiral acts as a radiation sensitizer[32] because it enhances the oxygenation of hypoxic tumors. The goal of adjunctive efaproxiral therapy is to achieve maximal concentrations of oxygen in the tumor tissue during administration of RT in order to decrease the hypoxic fraction of tumors, and thereby increase the radiation- or chemotherapy-responsiveness of malignant tumors.
The ability of efaproxiral to affect oxygenation of lung tumors is suggested by xenograft studies in mice with H226 human NSCLC cells, which showed that injection of efaproxiral to mice breathing supplemental oxygen increased tumor oxygenation and decreased gene expression of the hypoxia-inducible trancsription factor 1-alpha (HIF1-) when compared with controls.[33] Teicher et al,[31,34] have also demonstrated that in rats bearing the murine Lewis lung carcinoma, efaproxiral administration in conjunction with RT resulted in tumor growth delay and decreased numbers of lung metastases as compared with RT alone.
Because local control remains a problem for patients with locally advanced lung cancer who receive chemoradiotherapy, efaproxiral was added to a S-CRT regimen in an attempt to improve local control, while maintaining the lower toxicity rate (pneumonitis, esophagitis, and myelosuppression) previously observed with S-CRT in comparison with C-CRT.[10] By administering efaproxiral in this manner, a variation of C-CRT was created, in which efaproxiral was administered as the radiation sensitizer instead of a cytotoxic agent. To better assess the effect of the addition of efaproxiral to S-CRT, the results of our study (RT-010) were compared to data from the phase III, Radiation Therapy Oncology Group (RTOG) 94-10 study[10] in a matched-case comparison.
PATIENTS AND METHODS
Investigational Design
This was a phase II, nonrandomized, open-label, multicenter study ([Fig 1]) conducted in compliance with Good Clinical Practice and International Committee on Harmonization guidelines, and other applicable regulatory requirements. The protocol was approved by the institutional review boards or ethics committees of all participating institutions, and written informed consent was obtained from all patients before enrollment.
Patient Eligibility
Patients eligible for enrollment were men or nonpregnant women 18 years of age, with unresectable, histologically or cytologically documented NSCLC (stage IIIA or IIIB) and no previous surgical resection, chemotherapy, TRT, or efaproxiral treatment. Histology could include squamous cell carcinoma, adenocarcinoma (including bronchoalveolar cell), large-cell anaplastic carcinoma (including giant and clear-cell carcinomas), or poorly differentiated NSCLC. Patients with totally resected tumors; small cell carcinoma; or exudative, bloody, or cytologically malignant pleural effusions were excluded. Other eligibility requirements included Karnofsky performance status (KPS) 70; a computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of chest in addition to chest x-ray, and a CT or MRI scan of the brain; adequate lung function; exercise arterial oxygen saturation as measured by cutaneous pulse oximetry (SpO2) 90% while breathing room air; and adequate hematologic, hepatic, and renal function.
Treatment Plan
[Figure 1] provides information regarding the overall RT-010 treatment plan. For the chemotherapy regimen, the patients received 225 mg/m2 of intravenous (IV) paclitaxel over 3 hours in an outpatient setting. Immediately following the paclitaxel infusion, the patients received 6 area under the curve (AUC) of carboplatin, delivered as an IV infusion over 30 minutes. The same regimen of paclitaxel and carboplatin was repeated 3 weeks later on chemotherapy day 22. All patients were to receive two treatment cycles as induction chemotherapy. All chemotherapy dosing was based on the patient's actual weight. No dose escalation was allowed. Chemotherapy doses could have been reduced for hematologic and nonhematologic effects (sensory neuropathy, arthralgia/myalgia, hepatic toxicity, cardiac toxicity, hyperglycemia, hypersensitivity reactions, and other grade 2-4 toxicities). Dose adjustments were to be made according to the system showing the greatest degree of toxicity. Toxicity was graded using the Division of Cancer Treatment/National Cancer Institute (DCT/NCI) Common Toxicity Criteria. Treatment could be delayed no more than 2 weeks to allow recovery from toxicity. Dose adjustments for toxicity were made according to guidelines stipulated in the protocol.
The TRT began 3 to 4 weeks after completion of the chemotherapy dose schedule. TRT began between 1 and 8 days after chemotherapy days 43 to 50 (the stipulated range for resolution of any chemotherapy effects). The primary tumor and areas of known nodal disease received 64 Gy at 2.0-Gy fractions and five fractions per week for 32 fractions over 6 to 7 weeks. This was calculated at the point of maximal dose from all fields. The initial 50 Gy was delivered to target volume 1 (TV1). The final 14 Gy was to be delivered to a reduced volume targeting defined by target volume 2 (TV2).
All patients were treated with linear accelerator photon beams. The use of 60Co or electron beams was not permitted. It was recommended that photon energies of 12 MV or less be used because of lack of electronic equilibrium at air-tumor interfaces with higher energies. In institutions with only low (4 to 6 MV) and high (15 to 20 MV) energy beams, the higher energy could be used if it provided a better dose distribution. Minimal treatment distance was 80 cm source access distance. Localization films were to be taken on simulation units for all fields treated. Portal verification films taken on the treatment unit were required for all fields. When simulating the boost fields, barium contrast in the esophagus was required to document and minimize the volume of normal tissue irradiated. All doses were to be prescribed and calculated assuming tissue homogeneity (ie, without lung transmission correction). Doses were specified as the target dose, which was representative of the dose in the center of the target volume. Two target volumes were used. The first (TV1) included the mediastinum from thoracic inlet to subcarinal space, ipsilateral hilum, and bilateral mediastinal (N2) nodes. The supraclavicular fossa(e) were not to be treated routinely, but could have been treated when high paratracheal nodes are known to be involved by tumor or when the location of the primary tumor in the upper lobe made their avoidance difficult. Contralateral hilar coverage was not necessary unless gross adenopathy (> 1 cm) was present. This volume included the primary tumor and all lymph nodes of size 1.0 cm or greater on CT scan, with a margin of 1.5 to 2.0 cm. Volumes were based on a treatment planning CT scan obtained after induction chemotherapy. TV2 included only the known tumor volume as defined on CT (primary tumor and lymph node > 1.0 cm) and any nodal sites proven to be involved at surgical staging with a margin of 1.0 to 1.5 cm. Treatment planning was performed in accordance with the prescribed doses to each target volume, together with restrictions in dose to normal tissues that were provided in the protocol. The maximum spinal cord dose was to be determined, and the maximum cord dose should not have exceeded 50 Gy.
TRT quality assurance was conducted throughout the trial by the study chairperson (H.C.) and included review of films, field, and radiation dose data. More than 90% of the patients received TRT that was in accordance with the protocol guidelines.
Efaproxiral, chemical name: 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methylpropanoic acid monosodium salt, was supplied by Allos Therapeutics (Westminster, CO). Efaproxiral was infused over 30 minutes via a central venous access device, and TRT was administered within 30 minutes of the end of infusion. To optimize tumor oxygen delivery and to insure sufficient arterial oxygen saturation during the period when hemoglobin-oxygen binding affinity was reduced by efaproxiral, patients received continuous supplemental oxygen (4 L/min) via nasal cannula 5 minutes before efaproxiral administration, and throughout and after TRT. SpO2 was monitored pre–supplemental oxygen, preinfusion (on oxygen), and every 30 minutes until discharge. During dosing, supplemental oxygen was increased as needed to maintain SpO2 90%, and patients were discharged when SpO2 was 90% while breathing room air.
The initial daily dose of efaproxiral was 75 mg/kg. Dose reductions to 50 mg/kg or increases to 100 mg/kg were allowed, depending on patient tolerance. Efaproxiral dose reduction or omission was recommended if progressive prolongation of SpO2 recovery to 90% occurred, or if the SpO2 recovery period was more than 4 hours. If the patient's preinfusion SpO2 was less than 90%, then efaproxiral dose was omitted and the patient received TRT only. Doses omitted were not made up.
Efficacy Evaluations
The objectives of this study were to evaluate complete and partial response rates in the chest (radiation portal), overall survival (1-year, 2-year, and MST), time to disease progression inside and outside the chest (radiation portal), and toxicities/ adverse events associated with efaproxiral/TRT following induction chemotherapy.
Local control was assessed by evaluating progression-free survival and time to tumor progression inside and outside the radiation portal. Progression-free survival was defined as the period from the first day of induction chemotherapy to documented disease progression or death. Time to tumor progression was defined as the period from the first day of induction chemotherapy to documented disease progression, with death as a censoring event. These data were used to determine the site of initial progression. The investigators' determinations of tumor response and disease progression were used in the data analysis. Response and progression were assessed by MRI/CT scans performed at baseline and the 2- and 3-month routine follow-up visits. Investigators based their evaluations on bidimensional assessments, and the Eastern Cooperative Oncology Group Solid Tumor Response Criteria provided in the protocol.
Pattern of failure was based on investigator assessment and the location of first progression inside or outside the radiation portal. This information was used to determine time to progression and location of first progression inside and outside the radiation portal. If progression occurred both inside and outside the radiation portal within a span of 1 month, this was considered synchronous progression.
Survival time was defined as the period from the first day of induction chemotherapy to death. All patients were to be followed for survival until death, and surviving patients were followed for survival for a minimum of 28 months. The final date for inclusion of survival data in the analysis was January 6, 2003. Median potential follow-up time was calculated from the first day of chemotherapy to January 6, 2003. Rates for 1- and 2-year survival and Kaplan-Meier estimates of MST were determined.
Statistical analyses were conducted independently by the sponsor and by the RTOG statistics group (C.S.). For all statistical analyses, P values were two-sided, and a P value less than .05 was considered statistically significant. A statistical comparison of data from RT-010 with data from study RTOG 94-10 (S-CRT and C-CRT arms) was conducted to compare the efaproxiral study results with a historical control group. RTOG 94-10 is the largest trial ever conducted in locally advanced, unresectable NSCLC, with more than 600 patients randomly assigned to three treatment arms.[10] RTOG 94-10 compared a regimen of S-CRT (cisplatin and vinblastine) followed by standard TRT with a regimen of C-CRT with cisplatin and vinblastine administered with standard TRT. The standard TRT for these two arms was very similar to that used in RT-010. A third arm consisted of C-CRT with cisplatin and oral etoposide administered with twice-daily TRT (C-CRT bid). The log-rank test was used to compare survival data. Exact-matched cases were obtained by case-matching RT-010 patients with RTOG 94-10 patients by stage, KPS (exactly), and age (± 5 years). Cases were matched only once, and resampling was not performed. Once a data set was obtained, Kaplan-Meier estimates were performed and log-rank tests were conducted. A stratified Cox model, with each matched pair (RTOG-efaproxiral) as a stratum, and study group as the only independent factor, was used to estimate efaproxiral treatment effect.
Safety
Safety parameters were assessed throughout induction chemotherapy, efaproxiral/TRT treatment, and during the follow-up period until 2 years after the date of enrollment. Safety was assessed through monitoring treatment-emergent adverse events/toxicities (from induction chemotherapy, TRT, or efaproxiral treatments), and changes in clinical laboratory parameters, SpO2, vital signs, and physical examinations. Adverse events were graded by investigators with regard to severity and relationship to either chemotherapy or efaproxiral/TRT treatment, as described previously in Shaw et al.[32] Serious adverse events (SAEs) were defined as in Shaw et al.[32] Treatment-emergent laboratory abnormalities assigned a toxicity grade 2 or higher and representing an adverse change of 1 or more toxicity grade(s) from baseline, were considered "clinically significant."
Pharmacokinetics/Pharmacodynamics
Plasma and RBC efaproxiral concentrations were assayed to evaluate the pharmacokinetics of efaproxiral, and the pharmacodynamic effect was evaluated by quantifying the shift in PO2, at which hemoglobin was 50% saturated (p50), as determined by multipoint tonometry.[32] The pharmacodynamic end point was an increase in p50 of 10 mmHg. Pharmacokinetic/pharmacodynamic assays were performed on TRT day 1, and once per each TRT-week thereafter.
RESULTS
Patient Characteristics and Extent of Exposure
A diagram explaining the number of patients enrolled and analyzed is provided in [Figure 2]. Briefly, a total of 52 patients with unresectable stage IIIA or IIIB NSCLC from 13 institutions throughout the United States and Canada were enrolled from October 1998 to June 2000. One patient was deemed ineligible before starting chemotherapy, so 51 enrolled patients were analyzed: 27 stage IIIA and 24 stage IIIB patients. Forty-nine of these enrolled patients were eligible and were therefore included in the efficacy analysis. For the safety analysis, 51 patients were included in the analysis of events occurring during the chemotherapy period, and 47 of the 51 patients were included in the analysis of events occurring during the efaproxiral/TRT period. Demographic and pretreatment characteristics of the enrolled patients are presented in [Table 1]. For the 49 eligible patients treated with efaproxiral/TRT, 80% (39 of 49) completed 22 or more of the 32 planned efaproxiral doses. The median number of efaproxiral doses was 31.0, and the median efaproxiral dose was 75.1 mg/kg. The vast majority of patients received the full dose of chemotherapy (carboplatin:paclitaxel ratio) for both cycles 1 (94%:96%) and 2 (81%:85%).
Response
According to the investigators' assessments, at the 2-month follow-up evaluation, complete (CR) and partial (PR) responses were achieved by 6% (three of 49) and 69% (34 of 49) of patients, respectively. Therefore, the overall response rate (CR + PR) was 75% (37 of 49). Progressive disease (PgD) occurred in 4% (two of 49) of patients, and 6% (three of 49) of patients had stable disease. Seven patients did not have a 2-month response evaluation as assessed by the investigator, either because no scan was performed or no evaluation was provided.
Survival
The overall survival and progression-free survival estimates are based on data from all eligible patients (N = 49). [Table 2] summarizes the Kaplan-Meier estimates of overall survival, and [Figure 3] presents the Kaplan-Meier survival plot. The median potential follow-up time was 36.7 months. The overall survival rates at 1 and 2 years were 67% and 37%, respectively. The overall MST was 20.6 months (95% CI, 14.0 to 24.2 months).
MST was also analyzed according to stage, age, KPS, sex, response, dose received, and number of doses received. The MST for the stage IIIA (n = 26) and stage IIIB groups (n = 23) was 22.0 and 16.3 months, respectively. Patients receiving 21 or more efaproxiral doses had a longer MST than patients who received one to 20 doses (22.9 v 9.0 months, respectively). Patients with a response of CR at the 2-month follow-up had a longer MST than patients with a response of PgD (36.5 v 14.6 months, respectively).
[Table 3] summarizes the progression-free estimates for the RT-010 patient population. The overall progression-free survival rates (meaning patients with any progression regardless of location) were 67% at 6 months, 37% at 1 year, 16% at 2 years, and 12% at 3 years. Progression-free survival rates were slightly higher with respect to progression inside the radiation portal than outside the radiation portal. For the 1-year and 2-year estimates, the inside portal progression-free survival rates were 51% and 27%, respectively, and outside the portal, progression-free survival rates were 41% and 22%, respectively.
Site of Initial Progression
The site of initial progression was calculated based on investigator reports of progression dates. This analysis includes all reports of progression up to the date of January 6, 2003, regardless of when the progression occurred with respect to the 2-month follow-up evaluation, and these results are not a reflection of the percentages discussed here earlier for PgD. For 31% of patients (15 of 49), synchronous progression occurred (ie, progression both inside and outside the radiation portal within 1 month of each other). The site of initial progression was outside the radiation portal for 29% of patients (14 of 49), and inside the radiation portal for 12% (six of 49) of patients. Thus, for these 20 patients, 70% (14 of 20) experienced distant progression initially and 30% (six of 20) experienced local progression initially. Twenty-nine percent (14 of 49) of all patients had no progression dates reported, which meant either the patient died or was alive without progression and was therefore censored.
Safety
Adverse events that were considered possibly, probably, or definitely related to efaproxiral are summarized by toxicity grade in [Table 4]. The majority of efaproxiral-related adverse events were grade 1 toxicities. Sixteen of the 17 hypoxemia events were attributed to efaproxiral, and the majority of the cases of headache, nausea, vomiting, dizziness, and anemia were considered efaproxiral-related. Grade 3 and 4 toxicities that were considered related to efaproxiral and that occurred in more than one patient included transient hypoxemia (19%; nine of 47), radiation pneumonitis (11%; five of 47), and fatigue (4%; two of 47). There were no grade 3 or 4 efaproxiral-related events of radiation esophagitis.
Sixteen patients experienced one or more SAE, and six of these patients experienced events that were considered related to efaproxiral treatment. Thus, only 38% (six of 16) of patients who experienced SAEs had efaproxiral-related SAEs, which is less than 12% (six of 51) of the overall study participants. Hypoxia (hypoxemia; three patients) and radiation pneumonitis (two patients) were the only efaproxiral-related SAEs that occurred in more than one patient.
Clinically significant laboratory abnormalities were generally infrequent. Mean erythroid parameters (RBC count, hemoglobin, and hematocrit) showed decreases from baseline during treatment. The mean hemoglobin concentration was 12.0 g/dL at baseline, 11.75 g/dL on TRT day 31, and 13.34 g/dL at 3 months after efaproxiral/TRT completion. Anemia was reported as an adverse event in 18 patients. Adverse events were reported for increased serum creatinine in six patients, abnormal renal function in one patient, and acute renal failure was reported as an SAE in one patient.
Change in p50
In previous pharmacokinetic/pharmacodynamic studies of efaproxiral, maximum plasma and RBC concentrations of efaproxiral were seen at or near end-infusion[32]; therefore, end-infusion samples were considered to have approximated maximum concentration. The mean increases in p50 at end-infusion when patients received 75 mg/kg (n = 45) or 100 mg/kg (n = 20) were 8.1 and 11.0 mmHg, respectively, thereby demonstrating adequate pharmacodynamic effects (target: 10 mmHg). These effects were achieved at corresponding mean plasma concentrations of efaproxiral of 482.0 μg/mL (n = 44) and 563.9 μg/mL (n = 18), respectively, and at RBC concentrations of 419.9 μg/mL (n = 44) and 547.1 μg/mL (n = 18), respectively. As the TRT weeks progressed, there was no clinically relevant cumulative effect with respect to preinfusion efaproxiral concentrations in RBCs. This suggests the absence of study drug accumulation in the overall study population.
Comparison of RT-010 with RTOG 94-10
In a separate analysis conducted by the RTOG, survival results from the patients in RT-010 (n = 49) were compared to both the S-CRT arm (n = 201 patients) and the C-CRT arm (n = 201 patients) from the randomized, phase III NSCLC study, RTOG 94-10.[10]
Demographic characteristics were comparable among all three groups; however, a higher percentage of RT-010 patients (85%) had KPS of 90-100 versus S-CRT (77%) or C-CRT (75%) patients ([Table 1]). Also, a higher percentage of RT-010 patients (53%) had stage IIIA disease versus S-CRT (41%) or C-CRT patients (43%).
The MSTs for each group are as follows: RT-010 (20.6 months), S-CRT (14.6 months), and C-CRT (17.0 months; [Table 5]). To account for discrepancies in demographics and baseline characteristics, a matched-case analysis ([Table 6]) was performed, whereby all 49 RT-010 patients were matched to 49 S-CRT patients and 49 C-CRT patients by stage, KPS (exactly), and age (± 5 years). MSTs for the matched cases were similar to those presented in [Table 5] for all patients; hence, the greater MST calculated for efaproxiral patients was not due to imbalances in performance or disease status. A stratified Cox model showed a trend toward improvement in survival that favored study RT-010 over both the S-CRT (hazard ratio = 0.87) and C-CRT arms (hazard ratio = 0.76). The RT-010 study was not designed to identify statistically significant differences in survival; however, the results suggest that adding efaproxiral to S-CRT improves survival over S-CRT alone, and may provide survival rates at least comparable to C-CRT.
DISCUSSION
This study demonstrates the feasibility of incorporating efaproxiral into the S-CRT regimen. The objectives of this phase II open-label multicenter study were to assess the efficacy and safety of efaproxiral as a radiation sensitizer when administered to patients receiving S-CRT for locally advanced unresectable (stage IIIA and IIIB) NSCLC. Very encouraging response rate and MST results were observed. Patients in this study tended to have better survival than patients with similar characteristics in the randomized, phase III NSCLC study, RTOG 94-10. Safety evaluations confirmed that efaproxiral was well tolerated in patients receiving TRT when administered as daily IV doses over 30 minutes during the 6- to 7-week TRT course.
Historically, S-CRT has added a measurable survival increment in selected patients with NSCLC, and by most accounts, seems to be superior to TRT alone in treating distant disease and improving survival.[5-7] C-CRT provides improved local control and prolongs survival slightly over S-CRT[8-10]; however, C-CRT trials have reported very high mucosal toxicities, and the majority of patients do not tolerate the regimen well.[14,35]
The combined modality regimen of induction chemotherapy followed by efaproxiral and TRT was chosen in order to obtain the maximal systemic effect of chemotherapy and also impact local control through the use of efaproxiral with TRT. The design was based on the capability of efaproxiral to enhance the effect of radiation without increasing radiation toxicity rates. With an observed MST of 20.6 months for all eligible patients, and the favorable comparison of survival results to that of RTOG 94-10, the efficacy results of study RT-010 suggest the potential for efaproxiral to improve the survival rate of patients receiving induction chemotherapy followed by TRT. [Table 7] provides survival data from several studies of various chemoradiotherapy regimens. The survival results from RT-010 in comparison to these other studies further suggest a possible positive survival effect of efaproxiral with S-CRT. Of note, the RT-010 results also compare favorably with the sequential arm of the Locally Advanced Multimodality Protocol study, and the eligibility criteria and chemotherapy for this arm were nearly identical to that of RT-010.
It should be noted that the historical comparison of this phase 2 study with RTOG 94-10 was done retrospectively in order to better understand the RT-010 survival results. A comparison of local control for RT-010 versus RTOG 94-10 was not performed, due to differences in data collection and definitions of progression that would make the comparison uninformative. For the survival comparison, although a matched-case analysis was performed, the chemotherapy methods differed between the two studies. Comparisons of various platinum-based chemotherapy regimens in an S-CRT setting have not been reported in the literature, but it is generally accepted that most platinum-based combinations used for treating systemic disease are equivalent when administered before the RT phase of treatment in S-CRT. In addition, since this was a multicenter prospective study, the variations in treatment techniques among institutions were likely minimized.
Importantly, the safety profile in this study indicates that efaproxiral does not significantly increase radiation toxicity in comparison with other studies of S-CRT without efaproxiral.[11,36] Adverse events observed in these patients reflected the seriousness of their primary disease and the concurrent administration of TRT. The grade 3 or 4, treatment-related adverse events that occurred in more than one patient during the efaproxiral/TRT period were hypoxemia, radiation pneumonitis, and/or fatigue. Grade 3 or 4, treatment-related adverse events of hypoxemia and/or fatigue have also occurred in previous efaproxiral/RT studies.[32] Hypoxemia was expected because efaproxiral decreases the hemoglobin-oxygen binding affinity and reduces oxygen loading in the lungs at ambient oxygen pressure. Thus, the majority of patients receiving efaproxiral have predictable, dose-related, mild, and transient reductions in SpO2; however, most of these patients (approximately 75%) are asymptomatic and only require supplemental oxygen as treatment. The overall incidence of radiation pneumonitis in study RT-010 (severe 17%, eight of 47; includes treatment-related and non–treatment-related events) is higher than in published studies of S-CRT (range, 5% to 8%).[37-39] Whether this increase in the incidence of radiation pneumonitis in RT-010 was due to the administration of efaproxiral or to other factors, such as the combination of relatively high total radiation with large volumes, cannot be determined at this time.
a mechanistic point of view, efaproxiral is theoretically a superior radiation sensitizer compared with cytotoxic agents. This is because efaproxiral exerts its effect by reducing hypoxic regions within the tumor. Since normal tissues have no hypoxic regions, the likelihood of increased toxicity in normal tissue is small in comparison to cytotoxic agents. When cytotoxic agents are used as radiosensitizers, increased normal tissue toxicity is encountered due to direct cytotoxicity. The issue of lower toxicity may be of special significance in older patients and in those with lower performance status. Furthermore, because of its mechanism of action, efaproxiral has a different toxicity profile than RT. While the toxicities of CT overlap to some degree with those of RT, the side effects of efaproxiral are distinct from those of RT, making the efaproxiral/RT combination, in theory, more rational.
In conclusion, we hope to develop a new paradigm for the treatment of stage III NSCLC by the addition of efaproxiral to S-CRT. The results from this phase 2 study support the hypothesis that the addition of efaproxiral to S-CRT may decrease the rate of local recurrence without a significant increase in toxicity. This new combination represents a promising approach in NSCLC treatment and a randomized study should be pursued. Furthermore, these data suggest that efaproxiral may also be an ideal candidate for incorporation into C-CRT as it could potentially increase the efficacy of C-CRT without increasing the chemotherapy- and RT-related toxicities generally associated with C-CRT.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the followig authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Dr Julie Gelderloos for her expert assistance with the manuscript.
NOTES
Supported by Allos Therapeutics Inc, Westmister, CO.
Presented in part at the 10th World Conference on Lung Cacer, Vancouver, BC, August 2003; Federation of European Cancer Societies, Copenhagen, Denmark, September 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Centre H?spitalier Universitaire de Sherbrooke, Sherbrooke
H?pital Notre Dame
Montreal General Hospital
Jewish General Hospital, Montreal, Québec
Cross Cancer Institute, Edmonton
Tom Baker Cancer Centre, Calgary, Alberta, Canada
University of Arizona Health Sciences Center, Tucson, AZ
Radiation Therapy Oncology Group
Thomas Jefferson University, Philadelphia, PA
Johns Hopkins Hospital, Baltimore, MD
Tower Hematology/Oncology, Los Angeles, CA
University of Louisville, Louisville, KY
Allos Therapeutics Inc, Westminster, CO
ABSTRACT
PURPOSE: Efaproxiral (RSR13) reduces hemoglobin oxygen–binding affinity, facilitates oxygen release, and increases tissue pO2. We conducted a phase II multicenter study that assessed the efficacy and safety of efaproxiral when administered with thoracic radiation therapy (TRT), following induction chemotherapy, for treatment of locally advanced non–small-cell lung cancer (NSCLC).
PATIENTS AND METHODS: Fifty-one patients with locally advanced NSCLC were enrolled at 13 sites. Treatment comprised two cycles of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6), 3 weeks apart, followed by TRT (64 Gy/32 fractions) with concurrent efaproxiral (50 to 100 mg/kg). Survival results were compared with results of study Radiation Therapy Oncology Group (RTOG) 94-10.
RESULTS: Overall response rate was 75% (37 of 49 patients). Complete and partial response rates were 6% (three of 49 patients) and 69% (34 of 49 patients), respectively. Median survival time (MST) was 20.6 months (95% CI, 14.0 to 24.2); overall survival rates at 1- and 2-years were 67% and 37%, respectively. Survival results were compared with the sequential (S-CRT) and concurrent (C-CRT) chemoradiotherapy arms of RTOG 94-10. MSTs for cases matched by stage, Karnofsky performance status, and age were: RT-010, 20.6 months; S-CRT, 15.1 months; and C-CRT, 17.9 months. Grade 3 to 4 toxicities related to efaproxiral that occurred in more than one patient included transient hypoxemia (19%), radiation pneumonitis (11%), and fatigue (4%).
CONCLUSION: Addition of efaproxiral to S-CRT represents a promising approach in NSCLC treatment, and a randomized study should be pursued. The low incidence of grade 3 to 4 toxicities suggests that the use of efaproxiral instead of a cytotoxic agent, as a radiation sensitizer, may be advantageous.
INTRODUCTION
As the leading cause of cancer death in both men and women worldwide,[1] lung cancer requires innovative treatment regimens to improve treatment outcomes. Of all lung cancer cases, approximately 80% are non–small-cell lung cancer (NSCLC),[2] and 25% to 40% of NSCLC patients have stage III, locally advanced disease.[3] Most patients with stage III NSCLC are not candidates for surgical resection and are usually treated with a combination of chemotherapy and thoracic radiation therapy (TRT).[4] Despite such efforts, the majority of these patients relapse and die of their disease within 2 years of diagnosis.
For years, TRT alone was considered acceptable therapy for patients with locally advanced, unresectable stage III NSCLC. However, the therapy provided 5-year survival rates of only 5% to 7%, with a median survival time (MST) of 6 to 11 months.[5] In an attempt to improve these dismal survival results, the addition of full-dose induction chemotherapy administered before TRT was tested and shown to be superior to TRT alone.[5-7] The main objective of sequential chemoradiotherapy (S-CRT) was to improve patient outcome by reducing the risk of distant failure. Although S-CRT reduced the incidence of distant failure, there was no significant improvement in the rate of local control.[7] To improve local control, studies were also conducted in which lower dose chemotherapy was administered concurrently with TRT.[8-12] Concurrent chemoradiotherapy (C-CRT) was designed to maintain systemic control of distant disease while improving local control with the chemotherapy agent functioning as a radiation sensitizer. Randomized trials confirmed a reduction in the rate of local recurrence with C-CRT in comparison to S-CRT or TRT alone,[9,11] but there was no improvement in systemic control. Furthermore, patients treated with C-CRT experienced a higher incidence of grade 3 to 4 nonhematologic toxicities than patients treated with S-CRT.[10,13,14]
Hypoxic tumor cells are more resistant to radiation therapy (RT) than normal (oxic) cells,[15] and tumor hypoxia adversely affects the prognosis of patients receiving RT.[16-19] Oxygen measurements in human tumors have confirmed tumor hypoxia in glioblastoma multiforme (GBM),[20] brain metastases,[20,21] squamous cell carcinomas of the uterine cervix,[22] and head and neck[23] and breast carcinoma.[24] In lung tumors, an analysis conducted by Sasai et al[25] suggested an effect of hypoxia on tumor response to TRT, as arterial oxygen content was suggested to correlate with both local response and survival in NSCLC patients. Hemoglobin levels have also been shown to be statistically predictive indicators of survival in NSCLC patients, which may be related to a hypoxia effect on lung tumors.[26,27]
Efaproxiral (EFAPROXYN, RSR13) is a synthetic allosteric modifier of hemoglobin that noncovalently binds to the hemoglobin tetramer and decreases hemoglobin-oxygen binding affinity.[28] By this action, efaproxiral facilitates the release of oxygen from hemoglobin. Animal studies have demonstrated that efaproxiral increases tissue PO2[29,30] and oxygenation of tumors.[31] Efaproxiral acts as a radiation sensitizer[32] because it enhances the oxygenation of hypoxic tumors. The goal of adjunctive efaproxiral therapy is to achieve maximal concentrations of oxygen in the tumor tissue during administration of RT in order to decrease the hypoxic fraction of tumors, and thereby increase the radiation- or chemotherapy-responsiveness of malignant tumors.
The ability of efaproxiral to affect oxygenation of lung tumors is suggested by xenograft studies in mice with H226 human NSCLC cells, which showed that injection of efaproxiral to mice breathing supplemental oxygen increased tumor oxygenation and decreased gene expression of the hypoxia-inducible trancsription factor 1-alpha (HIF1-) when compared with controls.[33] Teicher et al,[31,34] have also demonstrated that in rats bearing the murine Lewis lung carcinoma, efaproxiral administration in conjunction with RT resulted in tumor growth delay and decreased numbers of lung metastases as compared with RT alone.
Because local control remains a problem for patients with locally advanced lung cancer who receive chemoradiotherapy, efaproxiral was added to a S-CRT regimen in an attempt to improve local control, while maintaining the lower toxicity rate (pneumonitis, esophagitis, and myelosuppression) previously observed with S-CRT in comparison with C-CRT.[10] By administering efaproxiral in this manner, a variation of C-CRT was created, in which efaproxiral was administered as the radiation sensitizer instead of a cytotoxic agent. To better assess the effect of the addition of efaproxiral to S-CRT, the results of our study (RT-010) were compared to data from the phase III, Radiation Therapy Oncology Group (RTOG) 94-10 study[10] in a matched-case comparison.
PATIENTS AND METHODS
Investigational Design
This was a phase II, nonrandomized, open-label, multicenter study ([Fig 1]) conducted in compliance with Good Clinical Practice and International Committee on Harmonization guidelines, and other applicable regulatory requirements. The protocol was approved by the institutional review boards or ethics committees of all participating institutions, and written informed consent was obtained from all patients before enrollment.
Patient Eligibility
Patients eligible for enrollment were men or nonpregnant women 18 years of age, with unresectable, histologically or cytologically documented NSCLC (stage IIIA or IIIB) and no previous surgical resection, chemotherapy, TRT, or efaproxiral treatment. Histology could include squamous cell carcinoma, adenocarcinoma (including bronchoalveolar cell), large-cell anaplastic carcinoma (including giant and clear-cell carcinomas), or poorly differentiated NSCLC. Patients with totally resected tumors; small cell carcinoma; or exudative, bloody, or cytologically malignant pleural effusions were excluded. Other eligibility requirements included Karnofsky performance status (KPS) 70; a computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of chest in addition to chest x-ray, and a CT or MRI scan of the brain; adequate lung function; exercise arterial oxygen saturation as measured by cutaneous pulse oximetry (SpO2) 90% while breathing room air; and adequate hematologic, hepatic, and renal function.
Treatment Plan
[Figure 1] provides information regarding the overall RT-010 treatment plan. For the chemotherapy regimen, the patients received 225 mg/m2 of intravenous (IV) paclitaxel over 3 hours in an outpatient setting. Immediately following the paclitaxel infusion, the patients received 6 area under the curve (AUC) of carboplatin, delivered as an IV infusion over 30 minutes. The same regimen of paclitaxel and carboplatin was repeated 3 weeks later on chemotherapy day 22. All patients were to receive two treatment cycles as induction chemotherapy. All chemotherapy dosing was based on the patient's actual weight. No dose escalation was allowed. Chemotherapy doses could have been reduced for hematologic and nonhematologic effects (sensory neuropathy, arthralgia/myalgia, hepatic toxicity, cardiac toxicity, hyperglycemia, hypersensitivity reactions, and other grade 2-4 toxicities). Dose adjustments were to be made according to the system showing the greatest degree of toxicity. Toxicity was graded using the Division of Cancer Treatment/National Cancer Institute (DCT/NCI) Common Toxicity Criteria. Treatment could be delayed no more than 2 weeks to allow recovery from toxicity. Dose adjustments for toxicity were made according to guidelines stipulated in the protocol.
The TRT began 3 to 4 weeks after completion of the chemotherapy dose schedule. TRT began between 1 and 8 days after chemotherapy days 43 to 50 (the stipulated range for resolution of any chemotherapy effects). The primary tumor and areas of known nodal disease received 64 Gy at 2.0-Gy fractions and five fractions per week for 32 fractions over 6 to 7 weeks. This was calculated at the point of maximal dose from all fields. The initial 50 Gy was delivered to target volume 1 (TV1). The final 14 Gy was to be delivered to a reduced volume targeting defined by target volume 2 (TV2).
All patients were treated with linear accelerator photon beams. The use of 60Co or electron beams was not permitted. It was recommended that photon energies of 12 MV or less be used because of lack of electronic equilibrium at air-tumor interfaces with higher energies. In institutions with only low (4 to 6 MV) and high (15 to 20 MV) energy beams, the higher energy could be used if it provided a better dose distribution. Minimal treatment distance was 80 cm source access distance. Localization films were to be taken on simulation units for all fields treated. Portal verification films taken on the treatment unit were required for all fields. When simulating the boost fields, barium contrast in the esophagus was required to document and minimize the volume of normal tissue irradiated. All doses were to be prescribed and calculated assuming tissue homogeneity (ie, without lung transmission correction). Doses were specified as the target dose, which was representative of the dose in the center of the target volume. Two target volumes were used. The first (TV1) included the mediastinum from thoracic inlet to subcarinal space, ipsilateral hilum, and bilateral mediastinal (N2) nodes. The supraclavicular fossa(e) were not to be treated routinely, but could have been treated when high paratracheal nodes are known to be involved by tumor or when the location of the primary tumor in the upper lobe made their avoidance difficult. Contralateral hilar coverage was not necessary unless gross adenopathy (> 1 cm) was present. This volume included the primary tumor and all lymph nodes of size 1.0 cm or greater on CT scan, with a margin of 1.5 to 2.0 cm. Volumes were based on a treatment planning CT scan obtained after induction chemotherapy. TV2 included only the known tumor volume as defined on CT (primary tumor and lymph node > 1.0 cm) and any nodal sites proven to be involved at surgical staging with a margin of 1.0 to 1.5 cm. Treatment planning was performed in accordance with the prescribed doses to each target volume, together with restrictions in dose to normal tissues that were provided in the protocol. The maximum spinal cord dose was to be determined, and the maximum cord dose should not have exceeded 50 Gy.
TRT quality assurance was conducted throughout the trial by the study chairperson (H.C.) and included review of films, field, and radiation dose data. More than 90% of the patients received TRT that was in accordance with the protocol guidelines.
Efaproxiral, chemical name: 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methylpropanoic acid monosodium salt, was supplied by Allos Therapeutics (Westminster, CO). Efaproxiral was infused over 30 minutes via a central venous access device, and TRT was administered within 30 minutes of the end of infusion. To optimize tumor oxygen delivery and to insure sufficient arterial oxygen saturation during the period when hemoglobin-oxygen binding affinity was reduced by efaproxiral, patients received continuous supplemental oxygen (4 L/min) via nasal cannula 5 minutes before efaproxiral administration, and throughout and after TRT. SpO2 was monitored pre–supplemental oxygen, preinfusion (on oxygen), and every 30 minutes until discharge. During dosing, supplemental oxygen was increased as needed to maintain SpO2 90%, and patients were discharged when SpO2 was 90% while breathing room air.
The initial daily dose of efaproxiral was 75 mg/kg. Dose reductions to 50 mg/kg or increases to 100 mg/kg were allowed, depending on patient tolerance. Efaproxiral dose reduction or omission was recommended if progressive prolongation of SpO2 recovery to 90% occurred, or if the SpO2 recovery period was more than 4 hours. If the patient's preinfusion SpO2 was less than 90%, then efaproxiral dose was omitted and the patient received TRT only. Doses omitted were not made up.
Efficacy Evaluations
The objectives of this study were to evaluate complete and partial response rates in the chest (radiation portal), overall survival (1-year, 2-year, and MST), time to disease progression inside and outside the chest (radiation portal), and toxicities/ adverse events associated with efaproxiral/TRT following induction chemotherapy.
Local control was assessed by evaluating progression-free survival and time to tumor progression inside and outside the radiation portal. Progression-free survival was defined as the period from the first day of induction chemotherapy to documented disease progression or death. Time to tumor progression was defined as the period from the first day of induction chemotherapy to documented disease progression, with death as a censoring event. These data were used to determine the site of initial progression. The investigators' determinations of tumor response and disease progression were used in the data analysis. Response and progression were assessed by MRI/CT scans performed at baseline and the 2- and 3-month routine follow-up visits. Investigators based their evaluations on bidimensional assessments, and the Eastern Cooperative Oncology Group Solid Tumor Response Criteria provided in the protocol.
Pattern of failure was based on investigator assessment and the location of first progression inside or outside the radiation portal. This information was used to determine time to progression and location of first progression inside and outside the radiation portal. If progression occurred both inside and outside the radiation portal within a span of 1 month, this was considered synchronous progression.
Survival time was defined as the period from the first day of induction chemotherapy to death. All patients were to be followed for survival until death, and surviving patients were followed for survival for a minimum of 28 months. The final date for inclusion of survival data in the analysis was January 6, 2003. Median potential follow-up time was calculated from the first day of chemotherapy to January 6, 2003. Rates for 1- and 2-year survival and Kaplan-Meier estimates of MST were determined.
Statistical analyses were conducted independently by the sponsor and by the RTOG statistics group (C.S.). For all statistical analyses, P values were two-sided, and a P value less than .05 was considered statistically significant. A statistical comparison of data from RT-010 with data from study RTOG 94-10 (S-CRT and C-CRT arms) was conducted to compare the efaproxiral study results with a historical control group. RTOG 94-10 is the largest trial ever conducted in locally advanced, unresectable NSCLC, with more than 600 patients randomly assigned to three treatment arms.[10] RTOG 94-10 compared a regimen of S-CRT (cisplatin and vinblastine) followed by standard TRT with a regimen of C-CRT with cisplatin and vinblastine administered with standard TRT. The standard TRT for these two arms was very similar to that used in RT-010. A third arm consisted of C-CRT with cisplatin and oral etoposide administered with twice-daily TRT (C-CRT bid). The log-rank test was used to compare survival data. Exact-matched cases were obtained by case-matching RT-010 patients with RTOG 94-10 patients by stage, KPS (exactly), and age (± 5 years). Cases were matched only once, and resampling was not performed. Once a data set was obtained, Kaplan-Meier estimates were performed and log-rank tests were conducted. A stratified Cox model, with each matched pair (RTOG-efaproxiral) as a stratum, and study group as the only independent factor, was used to estimate efaproxiral treatment effect.
Safety
Safety parameters were assessed throughout induction chemotherapy, efaproxiral/TRT treatment, and during the follow-up period until 2 years after the date of enrollment. Safety was assessed through monitoring treatment-emergent adverse events/toxicities (from induction chemotherapy, TRT, or efaproxiral treatments), and changes in clinical laboratory parameters, SpO2, vital signs, and physical examinations. Adverse events were graded by investigators with regard to severity and relationship to either chemotherapy or efaproxiral/TRT treatment, as described previously in Shaw et al.[32] Serious adverse events (SAEs) were defined as in Shaw et al.[32] Treatment-emergent laboratory abnormalities assigned a toxicity grade 2 or higher and representing an adverse change of 1 or more toxicity grade(s) from baseline, were considered "clinically significant."
Pharmacokinetics/Pharmacodynamics
Plasma and RBC efaproxiral concentrations were assayed to evaluate the pharmacokinetics of efaproxiral, and the pharmacodynamic effect was evaluated by quantifying the shift in PO2, at which hemoglobin was 50% saturated (p50), as determined by multipoint tonometry.[32] The pharmacodynamic end point was an increase in p50 of 10 mmHg. Pharmacokinetic/pharmacodynamic assays were performed on TRT day 1, and once per each TRT-week thereafter.
RESULTS
Patient Characteristics and Extent of Exposure
A diagram explaining the number of patients enrolled and analyzed is provided in [Figure 2]. Briefly, a total of 52 patients with unresectable stage IIIA or IIIB NSCLC from 13 institutions throughout the United States and Canada were enrolled from October 1998 to June 2000. One patient was deemed ineligible before starting chemotherapy, so 51 enrolled patients were analyzed: 27 stage IIIA and 24 stage IIIB patients. Forty-nine of these enrolled patients were eligible and were therefore included in the efficacy analysis. For the safety analysis, 51 patients were included in the analysis of events occurring during the chemotherapy period, and 47 of the 51 patients were included in the analysis of events occurring during the efaproxiral/TRT period. Demographic and pretreatment characteristics of the enrolled patients are presented in [Table 1]. For the 49 eligible patients treated with efaproxiral/TRT, 80% (39 of 49) completed 22 or more of the 32 planned efaproxiral doses. The median number of efaproxiral doses was 31.0, and the median efaproxiral dose was 75.1 mg/kg. The vast majority of patients received the full dose of chemotherapy (carboplatin:paclitaxel ratio) for both cycles 1 (94%:96%) and 2 (81%:85%).
Response
According to the investigators' assessments, at the 2-month follow-up evaluation, complete (CR) and partial (PR) responses were achieved by 6% (three of 49) and 69% (34 of 49) of patients, respectively. Therefore, the overall response rate (CR + PR) was 75% (37 of 49). Progressive disease (PgD) occurred in 4% (two of 49) of patients, and 6% (three of 49) of patients had stable disease. Seven patients did not have a 2-month response evaluation as assessed by the investigator, either because no scan was performed or no evaluation was provided.
Survival
The overall survival and progression-free survival estimates are based on data from all eligible patients (N = 49). [Table 2] summarizes the Kaplan-Meier estimates of overall survival, and [Figure 3] presents the Kaplan-Meier survival plot. The median potential follow-up time was 36.7 months. The overall survival rates at 1 and 2 years were 67% and 37%, respectively. The overall MST was 20.6 months (95% CI, 14.0 to 24.2 months).
MST was also analyzed according to stage, age, KPS, sex, response, dose received, and number of doses received. The MST for the stage IIIA (n = 26) and stage IIIB groups (n = 23) was 22.0 and 16.3 months, respectively. Patients receiving 21 or more efaproxiral doses had a longer MST than patients who received one to 20 doses (22.9 v 9.0 months, respectively). Patients with a response of CR at the 2-month follow-up had a longer MST than patients with a response of PgD (36.5 v 14.6 months, respectively).
[Table 3] summarizes the progression-free estimates for the RT-010 patient population. The overall progression-free survival rates (meaning patients with any progression regardless of location) were 67% at 6 months, 37% at 1 year, 16% at 2 years, and 12% at 3 years. Progression-free survival rates were slightly higher with respect to progression inside the radiation portal than outside the radiation portal. For the 1-year and 2-year estimates, the inside portal progression-free survival rates were 51% and 27%, respectively, and outside the portal, progression-free survival rates were 41% and 22%, respectively.
Site of Initial Progression
The site of initial progression was calculated based on investigator reports of progression dates. This analysis includes all reports of progression up to the date of January 6, 2003, regardless of when the progression occurred with respect to the 2-month follow-up evaluation, and these results are not a reflection of the percentages discussed here earlier for PgD. For 31% of patients (15 of 49), synchronous progression occurred (ie, progression both inside and outside the radiation portal within 1 month of each other). The site of initial progression was outside the radiation portal for 29% of patients (14 of 49), and inside the radiation portal for 12% (six of 49) of patients. Thus, for these 20 patients, 70% (14 of 20) experienced distant progression initially and 30% (six of 20) experienced local progression initially. Twenty-nine percent (14 of 49) of all patients had no progression dates reported, which meant either the patient died or was alive without progression and was therefore censored.
Safety
Adverse events that were considered possibly, probably, or definitely related to efaproxiral are summarized by toxicity grade in [Table 4]. The majority of efaproxiral-related adverse events were grade 1 toxicities. Sixteen of the 17 hypoxemia events were attributed to efaproxiral, and the majority of the cases of headache, nausea, vomiting, dizziness, and anemia were considered efaproxiral-related. Grade 3 and 4 toxicities that were considered related to efaproxiral and that occurred in more than one patient included transient hypoxemia (19%; nine of 47), radiation pneumonitis (11%; five of 47), and fatigue (4%; two of 47). There were no grade 3 or 4 efaproxiral-related events of radiation esophagitis.
Sixteen patients experienced one or more SAE, and six of these patients experienced events that were considered related to efaproxiral treatment. Thus, only 38% (six of 16) of patients who experienced SAEs had efaproxiral-related SAEs, which is less than 12% (six of 51) of the overall study participants. Hypoxia (hypoxemia; three patients) and radiation pneumonitis (two patients) were the only efaproxiral-related SAEs that occurred in more than one patient.
Clinically significant laboratory abnormalities were generally infrequent. Mean erythroid parameters (RBC count, hemoglobin, and hematocrit) showed decreases from baseline during treatment. The mean hemoglobin concentration was 12.0 g/dL at baseline, 11.75 g/dL on TRT day 31, and 13.34 g/dL at 3 months after efaproxiral/TRT completion. Anemia was reported as an adverse event in 18 patients. Adverse events were reported for increased serum creatinine in six patients, abnormal renal function in one patient, and acute renal failure was reported as an SAE in one patient.
Change in p50
In previous pharmacokinetic/pharmacodynamic studies of efaproxiral, maximum plasma and RBC concentrations of efaproxiral were seen at or near end-infusion[32]; therefore, end-infusion samples were considered to have approximated maximum concentration. The mean increases in p50 at end-infusion when patients received 75 mg/kg (n = 45) or 100 mg/kg (n = 20) were 8.1 and 11.0 mmHg, respectively, thereby demonstrating adequate pharmacodynamic effects (target: 10 mmHg). These effects were achieved at corresponding mean plasma concentrations of efaproxiral of 482.0 μg/mL (n = 44) and 563.9 μg/mL (n = 18), respectively, and at RBC concentrations of 419.9 μg/mL (n = 44) and 547.1 μg/mL (n = 18), respectively. As the TRT weeks progressed, there was no clinically relevant cumulative effect with respect to preinfusion efaproxiral concentrations in RBCs. This suggests the absence of study drug accumulation in the overall study population.
Comparison of RT-010 with RTOG 94-10
In a separate analysis conducted by the RTOG, survival results from the patients in RT-010 (n = 49) were compared to both the S-CRT arm (n = 201 patients) and the C-CRT arm (n = 201 patients) from the randomized, phase III NSCLC study, RTOG 94-10.[10]
Demographic characteristics were comparable among all three groups; however, a higher percentage of RT-010 patients (85%) had KPS of 90-100 versus S-CRT (77%) or C-CRT (75%) patients ([Table 1]). Also, a higher percentage of RT-010 patients (53%) had stage IIIA disease versus S-CRT (41%) or C-CRT patients (43%).
The MSTs for each group are as follows: RT-010 (20.6 months), S-CRT (14.6 months), and C-CRT (17.0 months; [Table 5]). To account for discrepancies in demographics and baseline characteristics, a matched-case analysis ([Table 6]) was performed, whereby all 49 RT-010 patients were matched to 49 S-CRT patients and 49 C-CRT patients by stage, KPS (exactly), and age (± 5 years). MSTs for the matched cases were similar to those presented in [Table 5] for all patients; hence, the greater MST calculated for efaproxiral patients was not due to imbalances in performance or disease status. A stratified Cox model showed a trend toward improvement in survival that favored study RT-010 over both the S-CRT (hazard ratio = 0.87) and C-CRT arms (hazard ratio = 0.76). The RT-010 study was not designed to identify statistically significant differences in survival; however, the results suggest that adding efaproxiral to S-CRT improves survival over S-CRT alone, and may provide survival rates at least comparable to C-CRT.
DISCUSSION
This study demonstrates the feasibility of incorporating efaproxiral into the S-CRT regimen. The objectives of this phase II open-label multicenter study were to assess the efficacy and safety of efaproxiral as a radiation sensitizer when administered to patients receiving S-CRT for locally advanced unresectable (stage IIIA and IIIB) NSCLC. Very encouraging response rate and MST results were observed. Patients in this study tended to have better survival than patients with similar characteristics in the randomized, phase III NSCLC study, RTOG 94-10. Safety evaluations confirmed that efaproxiral was well tolerated in patients receiving TRT when administered as daily IV doses over 30 minutes during the 6- to 7-week TRT course.
Historically, S-CRT has added a measurable survival increment in selected patients with NSCLC, and by most accounts, seems to be superior to TRT alone in treating distant disease and improving survival.[5-7] C-CRT provides improved local control and prolongs survival slightly over S-CRT[8-10]; however, C-CRT trials have reported very high mucosal toxicities, and the majority of patients do not tolerate the regimen well.[14,35]
The combined modality regimen of induction chemotherapy followed by efaproxiral and TRT was chosen in order to obtain the maximal systemic effect of chemotherapy and also impact local control through the use of efaproxiral with TRT. The design was based on the capability of efaproxiral to enhance the effect of radiation without increasing radiation toxicity rates. With an observed MST of 20.6 months for all eligible patients, and the favorable comparison of survival results to that of RTOG 94-10, the efficacy results of study RT-010 suggest the potential for efaproxiral to improve the survival rate of patients receiving induction chemotherapy followed by TRT. [Table 7] provides survival data from several studies of various chemoradiotherapy regimens. The survival results from RT-010 in comparison to these other studies further suggest a possible positive survival effect of efaproxiral with S-CRT. Of note, the RT-010 results also compare favorably with the sequential arm of the Locally Advanced Multimodality Protocol study, and the eligibility criteria and chemotherapy for this arm were nearly identical to that of RT-010.
It should be noted that the historical comparison of this phase 2 study with RTOG 94-10 was done retrospectively in order to better understand the RT-010 survival results. A comparison of local control for RT-010 versus RTOG 94-10 was not performed, due to differences in data collection and definitions of progression that would make the comparison uninformative. For the survival comparison, although a matched-case analysis was performed, the chemotherapy methods differed between the two studies. Comparisons of various platinum-based chemotherapy regimens in an S-CRT setting have not been reported in the literature, but it is generally accepted that most platinum-based combinations used for treating systemic disease are equivalent when administered before the RT phase of treatment in S-CRT. In addition, since this was a multicenter prospective study, the variations in treatment techniques among institutions were likely minimized.
Importantly, the safety profile in this study indicates that efaproxiral does not significantly increase radiation toxicity in comparison with other studies of S-CRT without efaproxiral.[11,36] Adverse events observed in these patients reflected the seriousness of their primary disease and the concurrent administration of TRT. The grade 3 or 4, treatment-related adverse events that occurred in more than one patient during the efaproxiral/TRT period were hypoxemia, radiation pneumonitis, and/or fatigue. Grade 3 or 4, treatment-related adverse events of hypoxemia and/or fatigue have also occurred in previous efaproxiral/RT studies.[32] Hypoxemia was expected because efaproxiral decreases the hemoglobin-oxygen binding affinity and reduces oxygen loading in the lungs at ambient oxygen pressure. Thus, the majority of patients receiving efaproxiral have predictable, dose-related, mild, and transient reductions in SpO2; however, most of these patients (approximately 75%) are asymptomatic and only require supplemental oxygen as treatment. The overall incidence of radiation pneumonitis in study RT-010 (severe 17%, eight of 47; includes treatment-related and non–treatment-related events) is higher than in published studies of S-CRT (range, 5% to 8%).[37-39] Whether this increase in the incidence of radiation pneumonitis in RT-010 was due to the administration of efaproxiral or to other factors, such as the combination of relatively high total radiation with large volumes, cannot be determined at this time.
a mechanistic point of view, efaproxiral is theoretically a superior radiation sensitizer compared with cytotoxic agents. This is because efaproxiral exerts its effect by reducing hypoxic regions within the tumor. Since normal tissues have no hypoxic regions, the likelihood of increased toxicity in normal tissue is small in comparison to cytotoxic agents. When cytotoxic agents are used as radiosensitizers, increased normal tissue toxicity is encountered due to direct cytotoxicity. The issue of lower toxicity may be of special significance in older patients and in those with lower performance status. Furthermore, because of its mechanism of action, efaproxiral has a different toxicity profile than RT. While the toxicities of CT overlap to some degree with those of RT, the side effects of efaproxiral are distinct from those of RT, making the efaproxiral/RT combination, in theory, more rational.
In conclusion, we hope to develop a new paradigm for the treatment of stage III NSCLC by the addition of efaproxiral to S-CRT. The results from this phase 2 study support the hypothesis that the addition of efaproxiral to S-CRT may decrease the rate of local recurrence without a significant increase in toxicity. This new combination represents a promising approach in NSCLC treatment and a randomized study should be pursued. Furthermore, these data suggest that efaproxiral may also be an ideal candidate for incorporation into C-CRT as it could potentially increase the efficacy of C-CRT without increasing the chemotherapy- and RT-related toxicities generally associated with C-CRT.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the followig authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Dr Julie Gelderloos for her expert assistance with the manuscript.
NOTES
Supported by Allos Therapeutics Inc, Westmister, CO.
Presented in part at the 10th World Conference on Lung Cacer, Vancouver, BC, August 2003; Federation of European Cancer Societies, Copenhagen, Denmark, September 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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