Japanese Journal of Clinical Oncology Advance Access originally published online on July 19, 2006
Japanese Journal of Clinical Oncology 2006 36(8):504-510; doi:10.1093/jjco/hyl064
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© 2006 Foundation for Promotion of Cancer Research
Phase I/II Trial of Hyperfractionated Accelerated Chemoradiotherapy for Unresectable Advanced Pancreatic Cancer
1 Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka, 2 Department of Radiology, Graduate School of Medicine, Osaka University, Suita, Osaka, 3 Department of Multidisciplinary Radiotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, 4 Department of Surgery, Cancer Center, Department of Molecular Medicine, Osaka National Hospital, National Hospital Organization, Osaka and 5 Department of Radiotherapy, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
For reprints and all correspondence: Shoji Nakamori, Chief Surgeon of Department of Surgery, Cancer Center, Head of Department of Molecular Medicine, Osaka National Hospital, National Hospital Organization, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan. E-mail: nakamori{at}onh.go.jp
Received February 16, 2006; accepted May 8, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: We conducted a Phase I/II study to evaluate the local efficacy and toxicity of hyperfractionated accelerated radiotherapy (HART) combined with 5-fluorouracil (5-FU) and cisplatin (CDDP) in patients with unresectable advanced pancreatic cancer.
Methods: Thirty-five patients (15 with Stage 4A and 20 with Stage 4B disease according to TNM classification) were enrolled between August 1997 and August 2001 into this Phase I/II trial. All patients received concurrent HART (1.5 Gy twice daily separated by 6 h for 5 days per week), 5-FU (375 mg/m2 given as continuous intravenous infusion), and CDDP (2 mg/m2 given as 30-min infusion just before each fraction of irradiation). In the Phase I trial, the total dose of radiation was escalated from 27 to 45 Gy.
Results: Twenty-one patients were enrolled in the Phase I study and six patients were given the final planned dose (45 Gy) which did not exceed the maximum tolerated dose. Eleven patients (52.4%) suffered from Grade 3 or worse neutropenia. Vomiting and mucositis were observed in 21 (100%) and 12 (57.1%) patients, respectively. An additional 14 patients were entered in the Phase II trial and received a total dose of 45 Gy, which is recommended in Phase I trial. Concerning the local tumor control of 20 patients with the recommended regimen, 7 patients (35%) achieved partial response, 10 (50%) remained stable and local progressive disease occurred in 3 (15%). The median survival time and the overall 1-year survival rate were 11.2 months and 40.0%, respectively, in 20 patients who received the recommended regimen. In Stage 4A patients, they were 13.0 months and 70.0%, respectively. The trend of toxicities in patients with the recommended regimen was almost the same as that observed in the Phase I study.
Conclusion: The chosen combined modality treatment was well tolerated, and showed an expected local efficacy for the treatment of unresectable advanced pancreatic cancer.
Key Words: pancreatic cancer • radiotherapy • chemotherapy • 5-fluorouracil • cisplatin
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Worldwide, over 200 000 people die annually of pancreatic cancer and the overall 5-year survival has remained as low as less than 5% (1). Although surgery is the only curative treatment modality, less than 20% of patients with pancreatic cancer are candidates for resection. Despite the efforts of the past decades, conventional treatment approaches, such as surgery, radiation, chemotherapy, combinations of these, have had little impact on the course of this aggressive neoplasm (2). At the time of diagnosis, locally advanced unresectable pancreatic cancer without clinical metastasis represents about 40% of pancreatic cancer (3). External beam irradiation with chemotherapy has been used regularly in patients with locally advanced unresectable pancreatic carcinoma because the results of previous randomized trials by Gastrointestinal Tumor Study Group (GITSG) indicated that concurrent external beam radiation therapy and chemotherapy resulted in a significantly longer survival time than radiotherapy (RT) (4) or chemotherapy alone (5). However, the median survival times (MSTs) even of patients treated with chemoradiotherapy (CRT) remain unsatisfactory. Although numerous trials using modified CRT approaches have been conducted in an attempt to improve the efficacy of the treatment, few regimens have demonstrated significant superiority over conventional CRT in randomized controlled trials (2,3). Therefore, there is a clear need to establish more effective CRT for locally advanced pancreatic cancer (LAPC).
Concerning RT, novel fraction schedules have been explored since the 1980s with the aim of improving local tumor control and survival without increasing late morbidity (6). In hyperfractionated radiotherapy (HRT), the dose per fraction is reduced and the total dose increased to give improved tumor control without increased late morbidity (6). By contrast, in accelerated radiotherapy (ART) the overall duration of RT is reduced to overcome repopulation of tumor cells during the course of treatment (6). More recently, hyperfractionated accelerated radiotherapy (HART) was designed to combine both a reduction in dose per fraction and a shortening of the overall time of RT in an effort to gain a therapeutic benefit without increasing the risk of complications. The randomized controlled trials using HART in squamous cell carcinoma of head and neck (SCCHN) and non-small-cell carcinoma of lung (NSCLC) led to encouraging results (7,8). There are several reports which showed the effect of HART with or without concurrent chemotherapy on pancreatic cancer (9–14). Although a few reports are available on these modified fraction schedules, HART with concurrent chemotherapy on pancreatic cancer still remains to be controversial. Recently, several in vitro and in vivo studies, including a clinical lung cancer study on concurrent CRT using 5-fluorouracil (5-FU) and cisplatin (CDDP), have proved that biochemical modulation effects between 5-FU and cisplatin CDDP are effective, where the maximum radiosensitizing effects are achieved by daily CDDP administration before each fraction of radiation (15–18). In consideration of these data, here we report in the results of a prospective Phase I/II study that was conducted to evaluate the local efficacy and toxicity of the HART combined with continuous 5-FU infusion and low dose of CDDP just before each fraction of irradiation in unresectable advanced pancreatic cancer.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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ELIGIBILITY
Patients with histologically and/or cytologically proven, locally advanced pancreatic carcinoma and/or metastatic disease were enrolled in this study. They were required to have a World Health Organization (WHO) performance status (19) of 0–1, and adequate functions of bone marrow (WBC count >4000/µl, platelet count >100 000/µl, hemoglobin >10 g/µl), renal (serum creatinine concentration <1.5 mg/dl, blood urea nitrogen <20 mg%) and hepatic functions (serum transaminase level <2x of the upper normal range) except hyperbilirubinemia due to obstructive jaundice. All patients had to have a measurable primary tumor that could be assessed by abdominal computed tomography (CT). All patients should be expected to live more than 3 months. Patients were excluded if they had serious or uncontrolled concurrent medical illness, or a history of other malignancies. No prior chemotherapy or radiation therapy was allowed. The local ethics committee approved this study. Informed consent was obtained from all patients according to institutional regulations.
Pretreatment evaluation included a complete medical history, physical examination, complete blood count, differential blood cell count, biochemistry analysis, chest X-ray, electrocardiogram (ECG) and CT of the abdomen.
RADIOTHERAPY
Radiotherapy targeted at primary pancreatic tumors was delivered with X-rays of 10–18 MV from a linear accelerator with 4-field technique. Gross tumor volume (GTV) was defined as the macroscopically abnormal area visualized on each CT image with contrast enhancement. GTV included the tumor as defined on CT image, as well as areas of potential or proven involved regional lymph nodes. Clinical target volume (CTV) was defined as the GTV plus a 10-mm margin in all directions to account for subclinical tumor spread. Radiotherapy was not targeted at distant metastatic lesions. Each treatment field was irradiated twice daily, 6 h apart, 5 days per week at 1.5 Gy per fraction (Fig. 1). In the Phase I trial, the starting radiation dose was 27 Gy in 18 fractions (dose level 1), and the subsequent dose levels were 33, 39 and 45 Gy (dose level 2, 3 and 4, respectively). Dose escalation was achieved by increasing the frequency of radiation by 4 fractions. The final planned dose level of the trial was 45 Gy in 30 fractions. In the Phase II trial, the patients received the fixed dose that was decided in the Phase I trial.
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CHEMOTHERAPY
Chemotherapy was administered concurrently with RT, using 5-FU 375 mg/m2/day given as continuous intravenous infusion, and CDDP 2 mg/m2 given as 30-min infusion just before each fraction of irradiation (Fig. 1). Sufficient hydration to ensure a urinary output of at least 100 ml/h before and 4 h after the infusion of CDDP was required. All patients with liver metastasis were treated with arterial infusion therapy of 5-FU for 5 days, 200 mg/m2/day by continuous hepatic arterial infusion after the course of HART-based CRT. In patients with only locally advanced disease without liver metastasis, no additional therapy was performed in case of no disease progression. The patients with disease progression received second-line chemotherapy with uracil-tegafur.
EVALUATION
Treatment toxicities were evaluated by analyzing the combined data of patients with locally advanced disease (Stage 4A) and those with metastatic disease (Stage 4B). Because RT was targeted only at primary pancreatic tumors and not at distant metastatic lesions in Stage 4B patients, we evaluated the local response rate by analyzing combined data of Stage 4A and 4B patients. The treatment efficacy against metastatic lesions was not evaluated in this study. Survival of Stage 4A and 4B patients were analyzed separately.
TOXICITY EVALUATION
Toxicity of the therapy was initially to be evaluated with World Health Organization Toxicity Criteria (WHO-TC) (20). After publication of the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2 (20), toxicity was also evaluated according to it. On completion of the study, all toxicities were reviewed and re-evaluated according to NCI-CTC ver.2. Toxicity grades and frequencies were unchanged under the two criteria. Dose-limiting toxicity (DLT) was defined as Grade 4 neutropenia, Grade > 3 thrombocytopenia, Grade > 3 anemia, Grade > 2 hemorrhage from the gastrointestinal tract or Grade > 3 toxicity in other organ system (except nausea/vomiting and hyperbilirubinemia secondary to biliary obstruction).
Patient cohorts had a minimum of three patients at each dose level. If none of the patients treated at a given dose level had DLT as defined above, patients were entered at the next dose level. If DLT was observed in one out of three patients, three additional patients were entered at that dose level. If one or two out of six patients had a DLT, patients were entered at the next dose level. If three or more of three to six patients had a DLT, the maximum tolerated dose (MTD) was considered to have been exceeded and escalation was discontinued.
RESPONSE EVALUATION
In this study, only local response of primary pancreatic tumors was analyzed because target lesions of current radiochemotherapy were primary tumors. For response evaluation, CT reassessments were repeated every 4 weeks. A complete response (CR) was defined as a total resolution of all evidence of tumor on two consecutive evaluations 4 weeks apart. A partial response (PR) required a 50% reduction in the maximum perpendicular tumor measurements for at least 4 weeks. Stable disease (SD) was defined as less than 50% reduction and less than 25% increase of measurable tumor lesions lasting for at least 8 weeks. Patients were considered to have progressive disease (PD) if the measurable tumor lesions increased by greater than 25% according to initial staging within the first 2 months of therapy.
STATISTICAL METHODS
This Phase I/II study was designed to evaluate the overall feasibility of, and the toxicity, local tumor response, and overall survival with, administration of the HART combined with chemotherapy using 5-FU and CDDP. The sample size for the Phase II trial was determined as follows. The threshold response rate was defined as 5% and the expected response rate was set as 25%. This study was regarded to be adequate to recruit a total of 20 patients assuming alpha error of 0.05 and beta error of 0.2 based on Simon two-stage Phase II design (21). Survival was calculated from the date of admission to the date of death or last follow-up. Survival curves were calculated by the Kaplan–Meier method. Statistical calculations were performed using StatView software (version 5.0).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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From August 1997 to August 2001, 35 patients were enrolled into this Phase I/II study.
PHASE I STUDY
PATIENT CHARACTERISTICS
A total of 21 patients were entered into the Phase I trial in four cohorts. The number of patients who were entered into the dose level 1, 2, 3 and 4 were 3, 6, 6 and 6, respectively. Their pretreatment characteristics are listed on Table 1. Eleven patients were male and 10 were female. Their median age was 64 years with a range of 49–78 years. Nine patients had a WHO performance status of 0, and 12 had a status of 1. Eleven patients had cancers located in the head of the pancreas, 9 had in the body and one had in the tail. Seven patients had Stage 4A disease and 14 had Stage 4B (12 patients had liver metastasis, one had both lung and distant lymph node metastasis, and one had distant lymph node metastasis) according to the TNM classification (5th edition) (22). Eight patients had undergone a biliary bypass procedure before treatment; seven endoscopic stenting and one cholecyctojejunostomy.
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TOXICITIES
Toxicities in Phase I trial are listed on Table 2. No DLT was observed in the first three patients treated at dose level 1. Hematological toxicities meeting the criteria for DLT occurred in three patients; Grade 4 neutropenia was observed in one of six patients at dose level 3 and 4, and Grade 3 anemia was observed in one of six patients at dose level 4. Non-hematologic toxicities meeting the criteria for DLT occurred in six patients, including one of six patients with Grade 3 vomiting at dose level 2, two of six patients with Grade 3 vomiting at dose level 3 and 4, and one of six patients with Grade 3 mucositis at dose level 2. In this Phase I study, 45 Gy, the final planned dose, does not exceed the MTD as defined in the protocol. Therefore, patients received 45 Gy irradiation in the subsequent Phase II study.
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PHASE II STUDY
PATIENT CHARACTERISTICS
Fourteen patients were enrolled onto the Phase II trial, and all of them received 45 Gy irradiation, which was recommended in Phase I trial. A total of 20 patients including 6 patients entered in the recommended dose level in the Phase I trial were evaluated for toxicities and treatment efficacy. Their pretreatment characteristics are listed on Table 3. Twelve patients were male and eight were female. Their median age was 65 years with a range of 49–78 years. Nine patients had a WHO performance status of 0, and 11 had a status of 1. Eleven patients had cancers located in the head of the pancreas, and nine had them in the body of the pancreas. Ten patients had Stage 4A disease and 10 had Stage 4B (all 10 patients had liver metastasis) according to the TNM classification. Seven patients had undergone a biliary bypass procedure before treatment (six endoscopic stenting and one cholecystojejunostomy). All patients completed the prescribed course of therapy. One patient with Stage 4A disease underwent pancreatoduodenectomy 1.5 years after the end of the treatment.
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TOXICITIES
Toxicities in 20 patients who received recommended dose irradiation are listed on Table 4. The results showed almost the same trend as observed in Phase I trial (Table 2). With regard to hematological toxicity, neutropenia was the most common. Granulocyte-colony stimulation factor (G-CSF) was administered to the 10 patients with Grade 3 and 4 neutropenia. Anemia was observed in 80% patients. Only two patients had Grade 3 anemia. For the non-hematological toxicity, vomiting was observed in all 20 patients. Mucositis was observed in 12 patients.
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RESPONSE AND SURVIVAL
Twenty patients who received recommended dose irradiation were evaluated for the treatment response. All of the 20 patients were assessable for local response and survival. CA19-9 values are available for all patients. Seven patients showed more than 50% reduction, seven showed a reduction less than 50% and six showed an increase in CA19-9 level. The MST of patients with Stage 4A and 4B were 13.0 and 5.0 months, respectively, according to Kaplan–Meier method. The overall 1-year survival rate was 70.0 and 10.0% in Stage 4A and 4B group, respectively. Figure 2 shows the overall survival curves for these two groups. As to the primary lesion, PR and SD were observed in 7 and 10 patients, respectively. Three patients had PD. All patients who complained of pain before treatment obtained improvement in the symptom during or after treatment.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Several prospective randomized trials have shown a benefit with CRT compared to either RT or chemotherapy alone in the management of LAPC (3). However, improvements are modest and local control remains a significant challenge.
In an attempt to enhance loco-regional control, we chose HART combined with continuous 5-FU and low dose of CDDP just before each fraction of irradiation. The rationale for this protocol are as follows: (i) HART could shorten the treatment duration without increasing the risk of complication (6); (ii) cytotoxic effects by continuous 5-FU administration were superior to bolus 5-FU administration (23); (iii) CDDP enhanced the cytotoxicity of 5-FU (the inhibition of methionine transport by CDDP increasing the formation of covalent ternary complex of thymidylate synthase (TS), dUMP and 5,10-methylene-tetrahydro-folinic-acid coupled with the acceleration of folinic acid metabolism, resulting in the enhancement of 5-FU cytotoxicity by TS inhibition) (15); (iv) 5-FU could act as a radiosensitizer and continuous 5-FU administration with radiation was more effective (24,25); (v) daily low-dose CDDP administration before each fraction of radiation maximized the radiosensitizing effects (16,17).
Several reports showed the results of HART or HRT for LAPC (Table 5). Schuster et al. (9) applied HART (three fractions of 1.0–1.1 Gy, total 69–70 Gy) without chemotherapy for 12 patients and reported no serious acute toxicity. However, the local response rate and the MST were 8.3% and 7.9 months, respectively. The GISTG reported on HRT (two fractions of 1.2 Gy, total 50.4 Gy) with bolus 5-FU infusion (350 mg/m2) on the first 3 and last 3 days of RT in 18 patients (10). The MST was 35 weeks and the 1-year survival rate was 39%. During the trial, 67% patients had a Grade 3 or worse toxicity. Prott et al. (11) treated 32 patients by HART (two fractions of 1.6 Gy, total 44.8 Gy) with 5-FU (600 mg/m2) and folinic acid (300 mg/m2) on the first 3 days of RT. The MST was 12.7 months. Luderhoff et al. (12) conducted a pilot study using a combination of HART (three fractions of 1.1 Gy, total 45–50 Gy) and continuous infusion of 5-FU (25 mg/kg/day) the first and third week. They treated 13 patients, and the local response rate and the MST were 23.1% and 36 weeks, respectively. More recently, Ashamalla et al. (13) and Ueno et al. (14) conducted HRT using relatively high dose of irradiation (two fractions of 1.1 Gy delivering a total 63.8 Gy and two fractions of 1.2 Gy delivering a total 45.6–64.8 Gy, respectively) combined with chemotherapy during RT course. Treatment duration was 4–6 weeks. The local response rate was 29.4 and 20.7%, respectively. The MST was 10 and 12.2 months, respectively, and the 1-year survival rate was 45.0 and 55.0%, respectively.
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In our Phase I study, the final planned dose (45 Gy) did not exceed the MTD as defined in the protocol. Therefore, patients received 45 Gy irradiation in the subsequent Phase II study. Six patients in the Phase I study and an additional 14 patients enrolled in the Phase II study received recommended dose of irradiation, and a total of 20 patients were evaluated for the local efficacy and survival: these patients consisted of 10 patients with locally advanced lesions (Stage 4A) and 10 patients with metastatic lesions (Stage 4B). The MST and the overall 1-year survival rate of all 20 patients were 11.2 months and 40.0%, respectively. The outcome of Stage 4A patients was relatively good: the MST and 1-year survival rate were 13.0 months and 70.0%, respectively, although the total dose of RT used in this study was almost equal or lower than that used in other HRT of HART trials (Table 5). Moreover, concerning primary tumors, 7 patients (35%) showed PR, 10 (50%) remained SD, and local PD was observed in only 3 (15%) patients. These findings encouraged us to perform further trials of HART-based CRT for Stage 4A patients. On the other hand, the results of Stage 4B patients were dismal. All patients diagnosed as Stage 4B had liver metastasis, and they all received additional treatment of continuous hepatic arterial infusion of 5-FU. The chosen treatment, however, did not improve the survival in patients with liver metastasis: the MST and 1-year survival rate were 5.0 months and 10.0%, respectively. Therefore, more effective treatment modalities are needed to control liver metastasis.
In our treatment schedule, patients could complete the treatment with a shorten time of only 3 weeks: this duration is 40% shorter than that of conventional treatments usually ranging over 5 weeks. The overall treatment time was important because the life expectancy of patients with advanced pancreatic cancer was very short. In this regard, 85.7% of the patients were discharged within 1 week after treatment. In addition, all of the patients who complained of disease-related pain before treatment experienced pain relief during and after treatment.
The toxicities observed in our study were not life-threatening. Neutropenia was the most common acute hematological toxicity. However, Grade 3 or worse neutropenia could be recovered promptly with G-CSF. Thrombocytopenia was predominantly mild to moderate (up to Grade 2). The most major acute non-hematological toxicity was vomiting. The patients suffering from Grade 3 or worse vomiting could be controlled by antiemetics. No patients required the parental support. Although the frequencies of neutropenia and vomiting were relatively high compared with other trials, all the side effects were manageable and did not require treatment interruption or dose reduction.
The local efficacy of the chosen treatment has urged us to perform further studies using HART combined with chemotherapy for LAPC patients. Based on the results of a prospective randomized trial, gemcitabine bas become the standard first-line agent in patients with advanced pancreatic cancer (26). In radiobiological models, gemcitabine has also been observed to be a potent radiosensitizer (27). However, gemcitabine could not be used for pancreatic cancer patients when we started this study. At present, gemcitabine should be used for a chemotherapieutic reagent against advanced pancreatic cancer, and current study will be helpful to design clinical trials using combined HART with gemcitabine for patients with LAPC.
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Acknowledgments |
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This study was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, Japan and Scientific Research from the Japan Society for the Promotion of Science.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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