Treatments for Recurring Glioblastoma (Part Three)

Here we are at the nineteenth episode of Ben Williams’ guide translation project on treatment options for Glioblastoma Multiforme. This is the third and final part of chapter 13 of the guide. In this episode we talk about rechallenging with Temodar, Optune device, other chemotherapy agents and possibly combined VAL-083. The advice is again to use this information to discuss it with the medical team that is following you. You can also point them to references to the supporting scientific works.
The Glioblastoma.it for CUSP-ND for Emanuele fundraising campaign continues, albeit very slowly. Once the translation of the guide has been completed, a single volume (the Italian translation) will be downloadable as an ebook or possibly purchased in paper format. The offers will be used for the above mentioned fundraising champaign. Meanwhile, select the link and share it in order to raise awareness as many people as possible. Is very important. Enjoy the reading.

Rechallenging with Temodar

When a therapeutic drug is not effective or becomes ineffective with continued use, the standard practice in oncology is to stop using the drug for that specific patient. However, one of the main exceptions to this general rule is to continue using the drug but with a different dosing schedule, usually with lower doses but given on a daily or more frequent basis. Part of the rationale for this approach is that continuous chemotherapy, even at low doses, will inhibit the growth of new blood vessels that feed the tumor (37, 38). The optimal dosage for this metronomic chemotherapy program remains to be established because dividing blood vessel cells are more sensitive to chemotherapy than dividing cancer cells, but are also much faster to recover when chemotherapy is stopped.
A German group administered metronomic programs with very low doses of Temodar to 28 patients with recurrent tumors after initial treatment with the standard protocol (four had previous treatment with CCNU or PCV) (46). A twice daily dose of 10 mg / square meter twice daily was administered in combination with 200 mg of Celebrex. PFS-6 was 43% and median survival was 16.8 months from relapse. Unlike the standard Temodar protocol, toxicity was virtually absent except for one patient who developed lymphopenia. An important feature of the metronomic program is that even after tumor progression was detected, patients were able to continue the program for several months before progression produced significant clinical problems. It should also be noted that a high percentage of patients (68%) had also undergone surgery before starting the metronomic program with temozolomide. It is impossible to assess how much this, as well as the use of Avastin following progression to other TMZ on a metronomic basis, contributed to the positive outcome of overall survival.
The positive results of the clinical study just described appear to conflict with a previous study that also used a metronomic program for 28 patients with recurrent GBM after a treatment with nitrosourea; here the PFS-6 value was only 19% and the median survival was 8.7 months (47). However, there are several important differences between the two studies. The first difference was the use of Celebrex in combination with the metronomic Temodar in the German study and the use of a much lower dose of Temodar. In the second study, the daily dose was 75 mg / square meter, almost double that used in the German study. Patients in the second study were also prescribed a break from chemotherapy after 7 weeks of treatment.
An equally important difference was that the patients in the second study had different treatment histories.
The alternating weekly schedule has also been studied in patients who relapsed after the standard protocol. In a study conducted in Germany (35), patients with high-grade gliomas who had failed the standard protocol were given 150 mg / m2. meter on days 1-7 and 15-21 of a 28-day cycle. The PFS-6 value was 43% and the median time to progression was 18 weeks (4.1 months).
Slightly less positive results with the alternate week program were obtained in a Dutch study of 24 patients with GBM (36), where the PFS-6 value was 29%. Given the small number of patients, however, it is difficult to know if the variation was due to random variability.
The RESCUE clinical trial, published in 2010, used a metronomic TMZ program of 50 mg / m2 for patients with recurrent malignant gliomas (364). 91 patients with glioblastoma were divided into three categories: B1) those who had tumor progression during the first six cycles of first-line TMZ; B2) those who have progressed during prolonged first-line TMZ cycles, ie beyond the sixth cycle; and B3) those who progressed at least 2 months after completion of first-line TMZ cycles. Median values ​​of PFS, PFS-6, and OS-12 were significantly better in groups B1 and B3 than in group B2, implying that patients with disease progression during the first six cycles or after successful completion of therapy frontline with TMZ can take advantage of the metronomic TMZ.

Optune (formerly NovoTTF) from Novocure

See Chapter 3 for details on the Optune device.

Other chemotherapy agents in case of recurrence

Although Temodar is now the drug to be used for the initial treatment of glioblastoma, most patients will receive minimal benefit. Patients who have failed the standard treatment protocol often switch to other chemotherapy drugs. These include nitrosoureas, BCNU and CCNU (and ACNU in Europe and Japan), as well as platinum-based drugs and irinotecan, a drug developed for colon cancer also known as CPT-11.
While BCNU has been the standard chemotherapy treatment for glioblastomas for decades, there has never been definitive evidence of its effectiveness. A recent study in patients with recurrent tumors after radiation treatment reported some evidence (190). Out of forty patients who received BCNU at the time of tumor recurrence after radiotherapy, the PFS-6 value was 17%, accompanied by considerable liver and lung toxicity. Even less promising results were produced in a small Australian study in which BCNU was administered to patients who had progressed while using temozolomide. In this study, treatment failed in 23 of 24 patients during the first six months (191).
Considering that BCNU and PCV (which contains CCNU, an oral cousin of BCNU) have never been shown to be effective, a somewhat surprising result has been reported using PCV on recurrent tumors after radiotherapy (and on some patients after radiotherapy and previous chemotherapy). In this relatively large study of 86 patients (192), PFS-6 was 38%, a value higher than that obtained by Temodar in a comparable setting, albeit with considerable toxicity. However, another study (193) using PCV for patients with recurrent cancers after treatment failure with Temodar reported a PFS-6 value of only 13%. A plausible explanation for the discrepancy between the two studies is the nature of the previous treatment that had failed.
A new member of the nitrosourea family is the fotemustina, now available in Europe. In a recent review of its use on a variety of programs to treat patients with recurrent cancers after treatment with the Stupp protocol, the PFS-6 value ranged from 26 to 44% (194). The best results were obtained by administering fotemustine every two weeks for five consecutive treatments at a dose of 80 mg / m2 followed by maintenance therapy every four weeks. The PFS-6 value was 61% with a median time to progression of 6.7 months (195). In an Italian study reported at the 2014 SNO meeting, patients who had not completed the initial standard protocol received either avastin or fotemustine at the time of relapse. Survival six months after relapse was the primary measure considered and was slightly higher for patients who used photemustine (322).
Platinum-based drugs cisplatin and carboplatin have also been used as single agents. Carboplatin has become the drug of choice because it has significantly lower toxicity to the eyes, ears and kidneys. In a representative carboplatin study (196), 4 of 29 patients with recurrent glioma had partial regression and 10 achieved disease stabilization. However, other studies using platinum-based drugs have produced highly variable results and the cause of the variability is not precisely identifiable.
One of the newer chemotherapy agents is CPT-11 (also known as irinotecan), which has been approved by the FDA for the treatment of colon cancer. Its application to gliomas was pioneered by Dr. Henry Friedman of Duke University and is now undergoing clinical trials in numerous other medical centers as well. The initial results of the study were that 9 of 60 patients with recurrent gliomas achieved a confirmed partial response, while a further 33 patients achieved disease stabilization for more than 12 weeks (197). However, the results reported by other studies were less positive (198, 199).
Like Temodar, CPT-11 is now being studied in various combinations with other chemotherapy regimens, most notably gliadel wafer, intravenous BCNU and Temodar itself. Some results are available on the combination of CPT-11 and BCNU, which produced a PFS-6 value of 30% for patients who failed initial temozolomide-based chemotherapy (200). An interesting aspect of CPT-11 is that the gastrointestinal toxicity it produces, which can be severe, is substantially attenuated by low doses of thalidomide (we have already discussed in the previous chapters on the use of thalidomide as a treatment agent in its own right). A recent study combining CPT-11 and thalidomide in patients who had failed chemotherapy with both temodar and nitrosourea produced a PFS-6 value of 28% (201). Finally, CPT-11 was combined with famousx, in patients with recurrent tumors, and produced a PFS-6 value of 25% (202).

VAL-083 (Dianhydrogalactitol)

Phase 2 and 3 studies are underway for the use of Val-083 or bifunctional alkylating chemotherapy in the case of recurrent glioblastoma. Since VAL-083 uses a different mechanism than other alkylating agents used for GBM (temozolomide and nitrosoureas) and causes DNA lesions in locations not subject to repair by the MGMT enzyme, it is hoped that VAL-083 will be effective independently of the MGMT status of tumors. VAL-083, also known as dianhydrogalactic, is approved in China for chronic myeloid leukemia (CML) and lung cancer. In addition to the two clinical trials of GBM, there is also an extended access protocol that can be used by patients who have run out of standard treatment options to obtain the drug outside of clinical trials.

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(196) Yung, W.K., et al. Intravenous carboplatin for recurrent malignant glioma: a phase II study. Journal of Clinical Oncology, 1991, Vol. 9, pp. 860-864. 
(197) Friedman, H. S. et al. Irinotecan therapy in adults with recurrent or progressive malignant glioma. Journal of Clinical Oncology, 1999, Vol. 17, 1516-1525. 
(198) Buckner, J. et al. A phase II trial of irinotecan (CPT-11) in recurrent glioma. Proceedings of the American Society of Clinical Oncology, 2000, Abstract 679A. 
(199) Chamberlain, M. C. Salvage chemotherapy with CPT-11 for recurrent glioblastoma multiforme. Journal of Neuro-oncology, 2002, Vol. 56, 183-188. 
(200) Brandes, A.A., et al. Second-line chemotherapy with irinotecan plus carmustine in glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: A Phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J. of Clinical Oncology, 2004, 22(23), 4727-4734. 
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Fine! I hope you enjoyed reading, I was as faithful as possible. A new chapter very soon! Only two are missing and then the translation of the guide will finally be complete.