BCNU (Carmustine) and Gliadel (Carmustine Wafers)

Property	Information
Drug Name	BCNU and Gliadel Wafers
FDA Approval	Yes
Used for	High-grade gliomas
Clinical Trial Phase	Phase III (Europe for Gliadel)
Clinical Trial Explanation	Not specified
Common Side Effects	Low blood counts, pulmonary problems, infection, and seizures for Gliadel
OS without	Not specified
OS with	Gliadel: 13.9 months median survival; Combination with TMZ: Median survival ranges from 17 to 20.7 months
PFS without	Not specified
PFS with	Not specified
Usefulness Rating	4
Usefulness Explanation	Not specified
Toxicity Level	3
Toxicity Explanation	Not specified

Notes: While Gliadel wafers alone offer modest improvement, combining them with the standard TMZ protocol seems to significantly improve outcomes.

From Ben Williams Book: BCNU (carmustine) and Gliadel (carmustine wafers)

The combination of Temodar with BCNU, the traditional chemotherapy for glioblastomas, has also been studied, but has been complicated by issues of toxicity and the optimal schedule of dose administration for the two drugs. However, a recent published report involving patients with tumors recurring after radiation but no prior chemotherapy failed to show any benefit of combining BCNU with Temodar, compared to Temodar alone, as the PFS-6 for the combination was only 21%, accompanied by considerable toxicity (53).

An important variation in the use of BCNU has been the development of polymer wafers �22

known as gliadel. A number of such wafers are implanted throughout the tumor site at the time of surgery. BCNU then gradually diffuses from the wafers into the surrounding brain. A possible problem with the treatment is that the drug will diffuse only a small distance from the implant sites, and thus fail to contact significant portions of the tumor. However, a phase III clinical trial has demonstrated that survival time for recurrent high- grade gliomas is significantly increased by the gliadel wafers relative to control subjects receiving wafers without BCNU, although the increase in survival time, while

statistically significant, was relatively modest (54). Probably the best estimate of the benefit of gliadel as an initial treatment comes from a randomized clinical trial, conducted in Europe (55), which reported a median survival of 13.9 months for patients receiving gliadel compared to a median survival of 11.6 months for patients implanted with placebo wafers. As with other forms of chemotherapy, larger differences were evident for long-term survival. After a follow-up period of 56 months, 9 of 120 patients who received gliadel were alive, compared to only 2 of 120 of those receiving the

placebo. However, the results were not reported separately for glioblastomas vs. other high-grade gliomas, suggesting that the outcome results would have been more modest for the glioblastoma patients alone.

When gliadel has been combined with the standard TMZ + radiation protocol, survival time seems to be significantly improved, as assessed in three different retrospective clinical studies. In the first, from the Moffitt Cancer Center in Florida (56), the combination produced a median overall survival of 17 months, and a 2-year survival rate of 39%. In a second clinical trial reported by Johns Hopkins, where gliadel was developed (57), 35 patients receiving the combination had a median survival time of 20.7 months and a 2-year survival of 36%. In a third trial conducted at Duke University (58), 36 patients receiving gliadel in addition to the standard TMZ protocol had a median survival of 20.7 months and a 2-year survival of 47%. The Duke cohort also received rotational chemotherapy (which included TMZ) subsequent to radiation. It is important to keep in mind that patients eligible to receive gliadel must have operable tumors, which excludes patients who have received a biopsy only and have a generally poorer prognosis as a result. The effect of this selection bias is difficult to evaluate but it is likely to account for a significant fraction of the improvement in survival time when gliadel +TMZ is compared to TMZ alone.

A major advantage of gliadel is that it avoids the systemic side effects of intravenous BCNU, which can be considerable, not only in terms of low blood counts but also in terms of a significant risk of major pulmonary problems. But gliadel produces its own side effects, including an elevated risk of intracranial infections and seizures. However, the lack of systemic toxicity makes gliadel a candidate for various drug combinations. Especially noteworthy is a recent phase II trial with 50 patients with recurrent tumors that combined gliadel with 06-BG, a drug that depletes the MGMT enzyme involved in repair of chemotherapy-induced damage, but also causes unacceptable bone marrow toxicity when chemotherapy is given systemically. Survival rates at six months, one year �23

and two years were 82%, 47%, and 10%, respectively (59) which seems notably better than the earlier clinical trial with recurrent tumors using gliadel without the 06-BG, in which the corresponding survival rates were 56%, 20%, and 10%. Median survivals were also notably improved by the addition of 06-BG (50.3 weeks versus 28 weeks).Property "Has original text" (as page type) with input value "BCNU (carmustine) and Gliadel (carmustine wafers)</br></br>The combination of Temodar with BCNU, the traditional chemotherapy for glioblastomas,</br>has also been studied, but has been complicated by issues of toxicity and the optimal</br>schedule of dose administration for the two drugs. However, a recent published report</br>involving patients with tumors recurring after radiation but no prior chemotherapy failed</br>to show any benefit of combining BCNU with Temodar, compared to Temodar alone, as</br>the PFS-6 for the combination was only 21%, accompanied by considerable toxicity (53).</br></br>An important variation in the use of BCNU has been the development of polymer wafers</br>�22</br></br>known as gliadel. A number of such wafers are implanted throughout the tumor site at the</br>time of surgery. BCNU then gradually diffuses from the wafers into the surrounding</br>brain. A possible problem with the treatment is that the drug will diffuse only a small</br>distance from the implant sites, and thus fail to contact significant portions of the tumor.</br>However, a phase III clinical trial has demonstrated that survival time for recurrent high-</br>grade gliomas is significantly increased by the gliadel wafers relative to control subjects</br>receiving wafers without BCNU, although the increase in survival time, while</br></br>statistically significant, was relatively modest (54). Probably the best estimate of the</br>benefit of gliadel as an initial treatment comes from a randomized clinical trial,</br>conducted in Europe (55), which reported a median survival of 13.9 months for patients</br>receiving gliadel compared to a median survival of 11.6 months for patients implanted</br>with placebo wafers. As with other forms of chemotherapy, larger differences were</br>evident for long-term survival. After a follow-up period of 56 months, 9 of 120 patients</br>who received gliadel were alive, compared to only 2 of 120 of those receiving the</br></br>placebo. However, the results were not reported separately for glioblastomas vs. other</br>high-grade gliomas, suggesting that the outcome results would have been more modest</br>for the glioblastoma patients alone.</br></br>When gliadel has been combined with the standard TMZ + radiation protocol, survival</br>time seems to be significantly improved, as assessed in three different retrospective</br>clinical studies. In the first, from the Moffitt Cancer Center in Florida (56), the</br>combination produced a median overall survival of 17 months, and a 2-year survival rate</br>of 39%. In a second clinical trial reported by Johns Hopkins, where gliadel was</br>developed (57), 35 patients receiving the combination had a median survival time of 20.7</br>months and a 2-year survival of 36%. In a third trial conducted at Duke University (58),</br>36 patients receiving gliadel in addition to the standard TMZ protocol had a median</br>survival of 20.7 months and a 2-year survival of 47%. The Duke cohort also received</br>rotational chemotherapy (which included TMZ) subsequent to radiation. It is important</br>to keep in mind that patients eligible to receive gliadel must have operable tumors, which</br>excludes patients who have received a biopsy only and have a generally poorer prognosis</br>as a result. The effect of this selection bias is difficult to evaluate but it is likely to</br>account for a significant fraction of the improvement in survival time when gliadel</br>+TMZ is compared to TMZ alone.</br></br>A major advantage of gliadel is that it avoids the systemic side effects of intravenous</br>BCNU, which can be considerable, not only in terms of low blood counts but also in</br>terms of a significant risk of major pulmonary problems. But gliadel produces its own</br>side effects, including an elevated risk of intracranial infections and seizures. However,</br>the lack of systemic toxicity makes gliadel a candidate for various drug combinations.</br>Especially noteworthy is a recent phase II trial with 50 patients with recurrent tumors</br>that combined gliadel with 06-BG, a drug that depletes the MGMT enzyme involved in</br>repair of chemotherapy-induced damage, but also causes unacceptable bone marrow</br>toxicity when chemotherapy is given systemically. Survival rates at six months, one year</br>�23</br></br>and two years were 82%, 47%, and 10%, respectively (59) which seems notably better than</br>the earlier clinical trial with recurrent tumors using gliadel without the 06-BG, in which</br>the corresponding survival rates were 56%, 20%, and 10%. Median survivals were also</br>notably improved by the addition of 06-BG (50.3 weeks versus 28 weeks)." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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