BCNU (Carmustine) For Brain Tumors

Last updated 12/12/2007

• Proprietary Name: BCNU
• USA Brand Name: Sterile Carmustine, FDA approved chemotherapy agent, NSC # 409962 (1977) (1,2)
• Active Ingredient: Carmustine (1, 2, 3)
• Distributed By: Bristol Myers Squibb Oncology/Immunology Division, A Bristol Myers Squibb Company, Princeton, NJ (3, 4)
• Common Names: BCNU, BiCNU, Carmustine (1, 2, 3)
• Classification: Alkylating Agent , Nitrosurea (1, 3)
• BCNU was FDA approved in 1977. (2)
• Usual Brain Tumor Dosage: As a single chemotheraputic agent - 150-200mg/m2 every 6 weeks (2)
• Delivery: Intravenous(2, 3) (Editor's Note: this review does not apply to the use of BCNU administered directly to the tumor bed via biodegradable wafers (Gliadel). Click HERE for details on Gliadel Wafers, or to CCNU, which is an oral drug that is related to BCNU)
• Costs: Apx. $100.00 per 100mgs, (4) Not including hospital, IV set up and physician charges relating to the treatment Potential Side Effects: Bone Marrow Suppression, Anemia, Diarrhea, Low White Blood Counts, Low Platelet Counts, Kidney Damage, Lung Damage (Pulmonary Toxicity), Mouth Soreness, Swallowing Difficulties (3, 5).
• Recommended dosages: 150-200 mg/m2 intravenously every 6 weeks, providing BCNU is being administered as a single chemotherapy agent alone in previously untreated patients. It may be given as a single dose or divided into daily injections such as 75 to 100 mg/m2 on two successive days. Subsequent dosage from the initial dose should be adjusted according to the hematologic response of the patient to prior doses. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks as hematologic toxicity is delayed and cumulative (3).
• Blood Brain Barrier: Due to the high lipid solubility and lack of ionization, BCNU can cross the blood brain barrier. However, BCNU is rapidly degraded, with no intact drug detectable after 15 minutes (3). According to the Physician's Desk Reference (3):
• BCNU is contained in a package including a vial of 10mg Carmustine and a vial containing 3mL sterile dilulent (Dehydrated Alcohol Injection, USP).
• It must be stored in a refrigerator before use; it decomposes rapidly at temperatures above 86 degrees F.
• Once reconstituted, it must be protected from light and used within 8 hours at room temperature.
• It must be administered from a glass container.

BCNU (Carmustine) Review

Prior to 1998

BCNU was utilized as a single treatment chemotherapy for many years on primary brain tumors. In retrospect, historic statistics did not support the long term effectiveness of BCNU as a single agent on brain tumors (6, 7, 8, 9, & 10). In addition, the combination of BCNU and radiotherapy when compared to other chemo agents combined with radiotherapy did not indicate it provided a significant improvement in long term (18 month) survival (11, 12). Furthermore the effectiveness of BCNU as a single agent given IV or IA appeared to be questionable and controversial (13, 14); however, it was hoped that BCNU might prove beneficial when coupled with additional, perhaps, lesser toxic drugs. Newer clinical trials using BCNU with a second agent were underway as research in this area moved into the new millennium.

1998-2006

In the past ten years various therapeutic strategies involving BCNU have been attempted including chemotherapy combinations using one or two other agents in addition to BCNU, various agents in combination both before and after radiation therapy, novel strategies utilizing autologous stem cell rescue following various treatments, as well as the use of recombinant interferon.

In 1998, a Phase 1 study of BCNU, Cisplatin, and oral etopside administered prior to and during accelerated hyperfractionated radiation therapy showed promise (15). A retrospective study that same year showed that IA BCNU-PV (procabazine and vincristine) as adjuvant therapy to surgery and radiotherapy among patients under 55 years of age increased survival markedly (16). In 1999, it was reported that loco-regional and systemic chemotherapy with cisplatin and BCNU prior to radiation therapy increased survival significantly as compared to those receiving only systemic chemotherapy prior to radiation therapy (17). Sequential versus concurrent BCNU chemotherapy and radiotherapy were examined for the effects on survival and toxicity but because of the toxicity of BCNU, concurrent chemo and radiotherapy treatments were not recommended (18). A promising therapy utilizing autologous stem cell rescue for children following chemotherapy was approved in 1999, but BCNU-related pulmonary toxicity prevented its utilization in this strategy (19). One of the first uses of tamoxifen in combination with BCNU did not show an increase in effectiveness (20). In 2000, a sequential chemo (BCNU and Cisplatin)-radiotherapeutic treatment showed promising results that supported earlier such studies (21). The novel use of recombinant interferon-alpha in combination with BCNU following radiation therapy was not more effective than BCNU alone following radiation (22). In an effort to overcome nitrosourea-resistant recurrent/progressive glioma, a treatment effort combining BCNU and O(6)bensylguanine was attempted but was unsuccessful in producing tumor regression (23). A Phase III study comparing three cycles of infusional BCNU and cisplatin followed by radiation to radiation therapy and concurrent BCNU, did not improve median survival, required more time in the hospital, and was associated with more serious toxicities than standard therapy (24). A 2004 study looking at the effectiveness of BCNU in combination with temozolomide did not show an increase in effectiveness over temozolomide alone (25). A separate study that year testing BCNU plus irinotecan (CPT-11) did not show any increase in effectiveness over irinotecan alone (26). Stereotactic radiosurgery followed by conventional radiotherapy with BCNU was no more effective than standard radiotherapy followed by BCNU; neither improving outcome nor quality of life (27). Although the initial BCNU studies had been conducted more than 30 years previously, a Phase II study on 40 patients with recurrent glioblastoma following surgery and standard radiotherapy showed that the standard BCNU regimen was comparable with that reported in the past and with the newest therapies, such as temozolomide. However, BCNU toxicity was high and recovery slow, thus compromising the administration of further drugs in patients with progressive disease (28). A combination of BCNU and cisplatin with cranial irradiation followed by PCV was moderately toxic and appeared to offer no obvious survival advantages compared with radiotherapy plus BCNU and cisplatin alone (29). In 2005, temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma exhibited promising activity with a good safety profile (30). In 2007, a retrospective study of patients with complete surgical resection treated with a high dose BCNU, followed with a an autologous hematopoietic stem cell rescue, then radiation 40 days later, did not show an improved outcome in comparison to standard treatments (31).

In summary, while BCNU has played a significant role for more than 30 years in standard chemotherapy for glioblastoma multiforme, it has significant toxicity concerns and more effective, less toxic agents have since been discovered. However, the use of biodegradable polymer wafers impregnated with BCNU (which limits its systemic toxicity) has demonstrated a statistical benefit and should be investigated more thoroughly (32).

REFERENCES

1. CTEP, Division of Cancer Treatment and Diagnosis (DCTD), NCI "Cancer Therapy Evaluation program" (3 Dec 98).
2. U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research, Office of information Technology, Division of Data Management and Services, "Approved Drug Products with Therapeutic Equivalence Evaluations" Electronic Orange Book (3 Dec 98).
3. Physicians' Desk Reference, 48th ed.(1994):651-3 "BiCNU"
4. Unrestricted Biomedical Research Grants Program "Bristol-Myers Squibb Unrestricted Biomedical Research Grants Program" (30 Nov 98).
5. O'Driscoll BR, Kalra S, Gattamaneni HR, Woodcock AA, "Late carmustine lung fibrosis. Age at treatment may influence severity and survival." Chest 1995 May;107(5):1355-7 PMID: 7750330, UI: 95269503
6. Lote K, Engeland T, Haber B, Stenwig B, et al., "Survival, prognostic factors, and therapeutic efficacy in low-grade glioma: a retrospective study in 379 patients." J Clin Oncol 1997 Sep;15(9):3129-40, PMID: 9294476, UI: 97440168
7. Halperin EC, "Malignant gliomas in older adults with poor prognostic signs. Getting nowhere, and taking a long time to do it." Oncology 1995 Mar;9(3):229-34 discussion 237-8, 243, PMID: 7669516, UI: 95399122
8. Nelson DF, Diener-West M, Horton J, Chang CH, Schoenfeld D, Nelson JS, "Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group." NCI Monogr 1988;(6):279-84, PMID 3281031, UI: 88175113
9. Grossman SA, Wharam M, Sheidler V, et al., "Phase II study of continuous infusion carmustine and cisplatin followed by cranial irradiation in adults with newly diagnosed high-grade astrocytoma." J Clin Oncol 1997 Jul;15(7):2596-603, PMID: 9215830, UI: 97358734
10. Solero, CL, Monfardini S, Brambilla C, Vaghi A, et al., "Controlled study with BCNU vs. CCNU as adjuvant chemotherapy following surgery plus radiotherapy for glioblastoma multiforme." Cancer Clin Trials 1979 Spring;2(1):43-8, PMID: 229983, UI: 80090259
11. Newton HB, Bromberg J, Junck L, Page MA, Greenberg HS, "Comparison between BCNU and procarbazine chemotherapy for treatment of gliomas." Journal Neuroncol 1993 Mar;15(3):257-63, PMID: 8360711, UI: 93367532.
12. Walker MD, Green SB, Byar DP, Alexander E Jr, et al., “Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery.” N Engl J Med, 303(23):1323-9 1980 Dec 4.
13. Bashir R, Hochberg FH, Linggood RM, Hottleman K, "Pre-irradiation internal carotid artery BCNU in treatment of glioblastoma multiforme." J Neurosurg 1988 Jun;68(6):917-9 PMID: 2836567, UI: 88229853
14. Kleinschmidt-DeMasters BD, Geier JM, "Pathology of high-dose intra-arterial BCNU." Surg Neurol 1989 June;31(6):435-43, PMID: 2541513, UI: 8924244
15. Rajkumar SV, Buckner JC, Schomberg PJ, Reid JM, et al., “Phase I and pharmacokinetic study of pre-irradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high grade gliomas.” Int J Radiat Oncol Biol Phys. 1998 Dec 1:42(5)969-75.
16. Gundersen S, Lote K, Watne K, “A retrospective study of the value of chemotherapy as adjuvant therapy to surgery and radiotherapy in grade 3 and 4 gliomas.” Eur J Cancer. 1998 Sep:34(10)1565-9.
17. Boiardi A, Silvani A, Pozzi A, Fariselli L, et al., “Interstitial chemotherapy plus systemic chemotherapy for glioblastoma patients: improved survival in sequential studies.” J Neurooncol. 1999 Jan:41(2)151-7.
18. Kleinberg L, Grossman SA, Piantadosi S, Zeltzman M, Wharam M, “The effects of sequential versus concurrent chemotherapy and radiotherapy on survival and toxicity in patients with newly diagnosed high grade astrocytomas.” Int J Radiat Oncol Biol Phys. 1999 Jun 1:44(3):535-43.
19. Grovas, AC, Boyett JM, Lindsley K, Rosenblum M, et al., “Regimen-related toxicity of myeloablative chemotherapy with BCNI, thiotepa, and etoposide followed by autologous stem cell rescue for children with newly diagnosed glioblastoma multiforme.” Med Pediatr Oncol. 1999 Aug:33(2):83-7.
20. Napolitano M, Keime-Guibert F, Monjour A, Lafitte C, et al., “Treatment of supratentorial glioblastoma multiforme with radiotherapy and a combination of BCNU and tamoxifen.” J Neruooncol. 1999:45(3):229-35.
21. Dazzi C, Cariello A, Giannini M, Del Duca M, et al., “A sequential chemo-radiotherapeutic treatment for patients with malignant gliomas.” Anticancer Res. 2000 Jan-Feb:20(1B):515-8.
22. Buckner JC, Schomberg PJ, McGinnis WL, Cascino TL, et al., “A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma.” Cancer. 2001 Jul 15:92(2)420-33.
23. Quinn JA, Pluda J, Doaln ME, Delaney S, Kaplan R et al. “Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma.” J Clin Oncol. 2002 May 1:20(9)2277-83.
24. Grossman SA, O’Neill A, Grunnet M, Mehta M, et al., “Phase III study comparing three cycles of infusional camustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustint in patients with newly diagnosed supratentorial gliblastoma multiforme.” J Clin Oncol. 2003 Apr 15;21(8)1485-91.
25. Prados MD, Yung WK, Fine HA, Greenberg HS, et al. “Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme.” Neuro Oncol. 2004 Jan;6(1):33-7.
26. Reardon DA, Quinn JA, Rich JN, Gururangan S, Vredenburgh J, et al. Phase 2 trial of BCNI plus irinotecan in adults with malignant glioma.” Neuro Oncol. 2004 Apr;6(2):134-44.
27. Souhami L, Seiferfeld W, Brachman D, Podgorsak EB, et al. “Randomized comparison of randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme.” Int J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):853-60.
28. Brandes AA, Tosoni A, Amista P, Nicoloardi L, Grosso D, et al. “How effective is BCNU in recurrent glioblastoma in the modern era? A Phase II trial.” Neurology. 2004 Oct 12;63(7):1281-4.
29. Liau, CT, Wei KC, Tseng CK, Jung SM. “Combination chemotherapy with carmustine and cisplatin followed by procarbazine, lomustine, and vincristine for adult high-grade astrocytoma.” Chang Gung Med J. 2005 Jan;28(1):16-23.
30. Barrie M, Couprie C, Dufour H, Figarella-Branger D, et al. “Temolozomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme.” Ann Oncol. 2005 Jul;16(7):1177-84 Epub 2005 Apr 27.
31. Bay JO, Linassier C, Biron P, Durando X, et al. “Does high dose carmustine increase overall survival in supratentorial high-grade malignant glioma?” Int J Cancer. 2007 Apr 15:120(8):1782-6.
32. Aoke T, Hashimoto N, Matsutani M. “Management of glioblastoma.” Expert Opin Pharmacother. 2007 Dec:8(18):3133-46