Other Chemotherapeutic and Anti-tumoral drugs for the treatment of Glioblastoma Multiforme

Here we are at the fifth episode of Ben Williams’ guide translation project on treatment options for Glioblastoma Multiforme. This is Chapter 4 of the guide that talks about lomustina, carmustina and gliadel wafer, platinum compounds, procarbazine, bevacizumab (Avastin), inhibitors of EGFR and gleevec. The advice is to use this information to discuss with the medical team that is taking care of you. In case you can also point them to the supporting scientific references. Enjoy the reading!

CCNU (lomustina)

A study in Germany combined TMZ with CCNU (lomustine), the nitrosourea component of the PCV combination (52). Patients (N = 39) received CCNU on day 1 of each 6-week cycle and TMZ on days 2-6. Eight patients received intensified doses of both drugs, with slightly better survival results (but with substantially increased toxicity). The results of all patients were then aggregated. Median survival time was 23 months and survival rates were 47%, 26%, 18% and 16% at 2, 3, 4, and 5 years, respectively. Four of the 39 patients did not have a recurrence at 5 years. Only 23 of 39 patients were evaluated for MGMT gene status. Those with methylated MGMT had a median survival of 34 months, while those with unmethylated MGMT had a median survival of only 12.5 months. These results, including a 5-year survival rate of 16%, are among the best reported to date, albeit with a relatively small number of patients. But it should also be noted that patients who had a recurrence have also received other therapies, which may have contributed substantially to their survival. The addition of CCNU to standard therapy for newly diagnosed glioblastoma is currently in phase 3 clinical trials in Germany.

These results, including a 5-year survival rate of 16%, are among the best reported to date, albeit with a relatively small number of patients. But it should also be noted that patients who had a recurrence have also received other therapies, which may have contributed substantially to their survival. The addition of CCNU to standard therapy for newly diagnosed glioblastoma is currently in phase 3 clinical trials in Germany.

BCNU (carmustina) and Gliadel (wafer with carmustina)

The combination of Temodar with BCNU, the traditional chemotherapy for glioblastomas, was also studied, but the experimentation was complicated by toxicity problems and the choice of the optimal dose schedule of the two drugs. However, a recently published report involving patients with recurrent tumors after receiving radiotherapy, and no previous chemotherapy showed no benefit from combining BCNU with Temodar, compared to Temodar alone, as the PFS-6 for the combination it was only 21%, accompanied by considerable toxicity. (53).

An important change in the use of BCNU has been the development of polymer wafers known as gliadel wafer. A number of these wafers are implanted in the tumor site at the time of surgery. The BCNU then gradually spreads from the wafers into the surrounding portion of the brain. A possible problem with this treatment is that the drug only spreads to a small distance from the implantation sites and therefore fails to reach significant portions of the tumor. However, a Phase III clinical trial showed that survival time for high-grade recurrent gliomas was significantly improved with the gliadel wafer compared to that of control subjects receiving BCNU-free wafers, although the survival time increased, although statistically significant, it was relatively modest (54). Probably the best estimate of the benefit of gliadel wafer 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 who received the wafer with the placebo. As with other forms of chemotherapy, major differences in long-term survival were evident. After a follow-up period of 56 months, 9 of the 120 patients who received the gliadel wafer were still alive, compared with only 2 of the 120 who received the placebo. However, the results were not reported separately for glioblastomas versus other high-grade gliomas, suggesting that the results would have been more modest for glioblastoma patients alone.

When the gliadel wafer was combined with the Stupp protocol, survival time appears to be significantly better as assessed in three different retrospective clinical studies. In the first, conducted by 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 study reported by Johns Hopkins, in which the gliadel wafer was developed (57), 35 patients who received the combination treatment had a median survival time of 20.7 months and a 2-year survival of 36%. . In a third study conducted at Duke University (58), 36 patients who received the gliadel wafer in addition to the standard TMZ protocol had a median survival of 20.7 months and a 2-year survival of 47%. Duke’s patients also received rotational chemotherapy (which included TMZ) after radiotherapy. It is important to keep in mind that patients eligible to receive gliadel must have operable tumors, which excludes patients who have only received a biopsy and who result in a generally poorer prognosis. The effect of this selection bias is difficult to assess but it is likely that a significant fraction of patients will obtain an improvement in survival time when the wafer together with TMZ is compared with the use of TMZ alone.

A major benefit 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 serious lung problems. Certainly the gliadel wafer also produces its side effects, including a high risk of infections and intracranial convulsions. However, the lack of systemic toxicity makes wafer gliadel a good candidate for various drug combinations. Of particular note is a recent phase II study with 50 patients with recurrent cancers that combined gliadel wafer with 06-BG, a drug that depletes the MGMT enzyme involved in repairing chemotherapy-induced damage but also causes toxicity. bone marrow is unacceptable when chemotherapy is administered systemically. Six-month, one-year, and two-year survival rates were 82%, 47%, and 10%, respectively (59), which appears significantly better than the previous clinical study with recurrent tumors using gliadel without 06-BG, in whose corresponding survival rates were 56%, 20% and 10%. Median survival was also significantly improved with the addition of 06-BG (50.3 weeks versus 28 weeks).

Platinum compounds

Improved results have also been reported compared to those obtained with Temodar when Temodar was combined with cisplatin. In a couple of clinical studies conducted in Italy (61, 62) with patients with recurrent tumors, the PFS-6 was 34% and 35%. A treatment protocol with newly diagnosed patients that also appears to have produced better results than Temodar as a single agent combined Temodar with both cisplatin and etoposide (VP-16), administered through the carotid artery (63). Cisplatin and etoposide were administered after surgery and were given for three cycles spaced every 3 weeks, followed by standard radiotherapy protocol plus low dose Temodar, then high dose Temodar on day 1-5 schedule of each month. For 15 patients studied, the median survival was 25 months.

Procarbazine

Temodar has also been combined with procarbazine (64). Although that study’s report did not include the PFS-6 statistic, it reported an unusually high rate of tumor regressions, suggesting that this combination may be effective.

Bevacizumab (Avastin)

The most notable development in drug combinations was the addition of the anti-angiogenic drug, Avastin (also known as bevacizumab), to the standard Stupp protocol. As will be discussed below, Avastin has FDA approval for the treatment of glioblastomas that have recurred or progressed after initial treatment. Several clinical trials have now investigated its combination with the standard protocol.

Recently, the Stupp protocol and the Stupp and Avastin protocol for newly diagnosed patients were compared in two large randomized phase III clinical trials. In the first of these (70), known as the AVAglio study, the median PFS was 10.6 months for those who also received Avastin compared with 6.2 months for those who only received the Stupp protocol, a statistically significant difference. significant. However, the median overall survival was no different (16.8 months versus 16.7 months). It should be noted that the patients in the control group received Avastin after tumor progression occurred, so it is also possible to compare Avastin administered early with Avastin administered after recurrence. The further findings were that 72% of the group that received Avastin early was alive at one year, compared with 66% of the control group, while the two-year survival was 34% versus 30%.

In the second of these trials (71), carried on by the RTOG consortium, the trial design was essentially similar to the AVAglio study, as were the results. Median PFS was 10 months for those who received Avastin compared with 7.3 months for the control group (again statistically significant), while the median overall survival was 15.7 months for the Avastin group compared with at 16.1 months for control, an insignificant difference.

The best interpretation of these results is that patients have a longer time without tumor progression and presumably a better quality of life when Avastin is used as part of initial treatment. However, there is no overall survival benefit, compared to using Avastin only when a recurrence is detected. A further feature of the results, not emphasized by the authors of the reports, is that overall survival times were not better, indeed in some cases they were even worse, than those obtained with the Stupp protocol alone.

EGFR inhibitors: Iressa, Tarceva and Erbitux (gefitinib, erlotinib and cetuximab)

These three drugs, which have FDA approval for different types of cancer, have the common feature of targeting a growth signaling channel known as epidermal growth factor. The overexpression or mutation of EGF receptors is involved in the growth of many different types of cancer, including more than half of glioblastomas. In general, the use of these drugs as single agents has produced disappointing results, although there have been occasional cases of long-term survival. More promising results occurred when EGFR inhibitors were used in combination with the Stupp protocol.

When Tarceva was added to the standard Temodar protocol for newly diagnosed patients, median survival was 15.3 months (N = 97) in one study (72) and 19.3 months (N = 65 ) in a second study (73). The results of the second study were compared with two previous phase II studies involving a similar patient population, in which Temodar was combined with thalidomide or accutan. Median survival for these studies was 14.1 months.

The moderately positive results of the study just described conflict with a very similar study (N = 27) conducted at the Cleveland Clinic (74). In that study, median survival was only 8.6 months, significantly worse than the results obtained when temodar was used alone. How conflicting results can be reconciled is unclear.

Erbitux (also known as cetuximab) is a monoclonal antibody, which differs from Iressa and Tarceva, which are small molecules. Now, monoclonal antibodies are not thought to cross the blood-brain barrier, so it would be expected that Erbitux was ineffective against brain tumors. As a single agent, this appears to be true, as PFS-6 was only 10% for patients with high-grade recurrent gliomas (75). But when Erbitux was added during radiotherapy to the standard temozolomide protocol for 17 newly diagnosed patients (76), 87% of the patients were alive at the end of one year and 37% were progression-free. Median survival time was not yet available at the time of publication of the report. It is important to note that some researchers believe that radiation temporarily disrupts the blood-brain barrier.

An important development to identify patients who might respond to Tarceva came from a study (77) of glioma patients whose cancer conditions were also evaluated for their levels of a second protein called PKB / AKT. This is a signaling channel that results from the inactivation of the PTEN gene, a tumor suppressor gene commonly mutated in glioblastomas. None of the tumors with high levels of PKB / AKT responded to treatment with Tarceva, while 8 of 18 tumors with low levels responded to treatment. A refinement of this approach tested three different proteins: PTEN expression, EGFR expression and an EGFR protein mutation known as EGFR variant III (78). The level of EGFR was not related to the clinical outcome, while the co-expression of EGFR variant III and PTEN strongly predicted the clinical outcome.

Since PKB / AKT inhibition is likely to increase the efficacy of EGFR inhibitors, a treatment strategy currently being investigated is the combination of EGFR inhibitors with rapamycin (trade name rapamune, generic name sirolimus), an existing drug used for organ transplants to suppress the immune system and prevent organ rejection, but also inhibits the mTOR 1 complex, a promoter of AKT downstream tumor growth. A phase I study (79) combined Iressa with rapamycin for 34 patients (25 GBM) with recurrent cancers; two patients had partial tumor regression and 13 patients became chronic of the disease. PFS-6 was 24%. A second clinical study (80) with 28 heavily pretreated patients with low performance status (median Karnofsky score of 60) administered Iressa or Tarceva in combination with rapamycin, with the result that 19% of patients had tumor regression while 50% had stable disease, with a PFS-6 value of 25%. However, a third clinical study (81) combining tarceva and sirolimus for recurrent GBM had much worse results, with a PFS-6 value of only 3%.

Previous results from the use of EGFR inhibitors for the treatment of GBM range from moderately positive efficacy to minimal efficacy. The reasons for this variability are not obvious, as the effectiveness of the treatment probably depends on numerous genetic markers. Therefore, without a genetic analysis of individual tumors, it is difficult to understand what to recommend.

A recent paper (83) of potential greater significance noted that tumors may not respond to anti-EGFR drugs due to gene activation for a second growth factor known as insulin-like growth factor receptor I (IGF1R) . IGF1R has also been suggested as a source of resistance to tamoxifen and various other treatment agents. It is noteworthy, therefore, that two of the supplements to be discussed, silibinin and lycopene, are known to inhibit IGF-I. This suggests that silibinin and lycopene could substantially increase the effectiveness of any treatment that is based on EGFR inhibition. Metformin, a widely used diabetes drug, is also known to reduce the level of IGF-1 and is currently being studied as a treatment for several types of cancer.

An important question is how the efficacy of EGFR inhibitors correlates with the previously discussed results that Temodar’s metronomic programs produce a large improvement in survival for GBMs that have EGFR overexpression. All of the clinical trials discussed in this section have been based on the standard Temodar program, so it is unclear whether a metronomic program can produce different results.

Gleevec (imatinib)

Gleevec (also known as imatinib), a small molecule that targets a specific gene involved in the growth of a form of leukemia, has sparked considerable interest for its unprecedented efficacy. As will be discussed below, this general strategy of identifying growth signals for tumor growth and then attacking those signals, or their receptors, is one of the major new areas of cancer research. Such growth signaling channels are often involved in different types of cancer. Although Gleevec was developed specifically for chronic myeloid leukemia, it has also been shown to inhibit a more general type of growth signal, platelet-derived growth factor (PDGF), which is also involved in the growth of gliomas and other forms. cancer (e.g. small cell lung cancer).

The generally disappointing results obtained using gleevec for brain tumors may have several reasons. The drug may not cross the blood-brain barrier easily and may generate different resistance mechanisms than other agents used in treatment. In the study of gleevec for leukemia, for example, high levels of autophagy were observed, which can be inhibited by the concomitant use of chloroquine or other autophagy inhibitors.

An important variation in the use of gleevec has been to limit its use to patients with recurrent tumors who have tested positive for the overexpression of the platelet-derived growth factor receptor (90). PDGFR is overexpressed in 50-65% of cancers, particularly in secondary glioblastomas, which are thought to have evolved from lower grade cancers (in contrast to newly diagnosed glioblastomas). For this limited patient population, the PFS-6 value was 53%.

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I hope you enjoyed reading, I have been as faithful as possible. A new chapter very soon!