This message is very large, so I decided to publish it in a separate topic.
I analyzed the dose, schedule and mode of administration of bortezomib in successful and failed trials.
As can be seen, only in this successful study (Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy > https://www.ncbi.nlm.nih.gov/pubmed/29722661) bortezomib was used during radiation therapy. As expected, bortezomib is a radiosensitizer. Further, bortezomib was administered very long - up to 24 cycles (4 times in 28 days) or until progression. Also, perhaps the difference is that in this study from the 10th month bortezomib was administered subcutaneously.
I wrote out some details of each study. The only successful study:
Phase II Study of Bortezomib in Combination with Temozolomide and Regional
Radiation Therapy for Upfront Treatment of Patients with Newly-Diagnosed
Glioblastoma Multiforme: Safety and Efficacy Assessment
https://www.ncbi.nlm.nih.gov/pubmed/29722661
"Bortezomib is given intravenously/subcutaneously at 1.3 mg/ m² on days 1, 4, 8, 11, 29, 32, 36, and 39 during radiation as early as 14 days after surgery. Temozolomide is given daily (75mg/m2) during radiation, followed by 5 days out of 28 with a dosage of 150-200 mg/m2, for up to 24 cycles. Bortezomib at 1.3 mg/m2 is given on days 1, 4, 8, and 11 of each subsequent 28 day cycle. Both bortezomib and temozolomide will continue until progression or up to 24 cycles.
Bortezomib was initially given via intravenous (IV) infusion, but the protocol was later modified to subcutaneous (SC) injection at ~10 months after the first patient had begun treatment (e.g., August 2012), due to the reported similar efficacy with improved safety profile (11, 12).
Our data were encouraging for newly diagnosed GBM when bortezomib was combined with radiation therapy and temozolomide. In preclinical models, bortezomib has been shown to be a radiosensitizer. That could be one of the reasons for lacking of efficacy in the treatment of recurrent GBM with bortezomib and vorinostat (a histone deacetylase inhibitor) when radiotherapy was not used."
It is unclear, however, what effect on the duration of survival was provided by the treatment after the recurrence:
"Among all 24 patients, 3 had no progression at the time of the last follow-up and 1 lost followup. The remaining 20 patients had documented recurrence. The treatments for recurrence were at attending physician’s discretion. For first recurrence, 4 patients were treated with temozolomide re-challenge, 9 with bevacizumab single agent, 4 with bevacizumab plus lomustine (CCNU), 1 with bevacizumab plus onartuzumab, 1 with bevacizumab plus pembrolizumab, and 1 with nivolumab. For further tumor progression, treatment therapies consisted of traditional chemotherapy agents (CCNU, carboplatin or etoposide) with and without bevacizumab. Four patients received stereotactic radiation therapy during further recurrences."
Failed tests or without any outstanding result:
A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/26285768
A minimum of 4 weeks after radiation and full recovery after surgery were required.
Each cycle of therapy consisted of 6 weeks of oral tamoxifen 120 mg twice daily and intravenous bortezomib 1.3 mg/m2 on days 3, 6, 10, 13, 24, 27, 31, and 34 of every 6-week cycle.
A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/27300524
All patients received bortezomib 1.7 mg/m2 intravenously (IV) on day 1, 4 and 8. Patients underwent surgical resection of their tumor on day 8 or 9. Patients started TMZ 75 mg/m2 orally on days 1–7 and 14–21 and bortezomib 1.7 mg/m2 IV on days 7 and 21. Each post surgery cycle was 4 weeks.
Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma
https://www.ncbi.nlm.nih.gov/pubmed/27502784
The three agents were administered in 42 day cycles as shown in Fig. 1. Bortezomib was given at 1.3 mg/m2 on day 1 of weeks 1–4. Bevacizumab was given at a dose of 10 mg/kg on day 1 of weeks 1, 3, and 5. Temozolomide was given at doses of 25 mg/m2 (Group 1), 50 mg/m2 (Group 2), or 75 mg/m2 (Group 3) on days 1–28 of each cycle.
___________________________
I was also interested in this article, where it was concluded that "combination of bortezomib and autophagy inhibitors may shed new light on glioblastoma treatment."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840293/
The open question remains about the use of bortezomib in a cocktail for MGMT-methylated patients only after radiotherapy.
I analyzed the dose, schedule and mode of administration of bortezomib in successful and failed trials.
As can be seen, only in this successful study (Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy > https://www.ncbi.nlm.nih.gov/pubmed/29722661) bortezomib was used during radiation therapy. As expected, bortezomib is a radiosensitizer. Further, bortezomib was administered very long - up to 24 cycles (4 times in 28 days) or until progression. Also, perhaps the difference is that in this study from the 10th month bortezomib was administered subcutaneously.
I wrote out some details of each study. The only successful study:
Phase II Study of Bortezomib in Combination with Temozolomide and Regional
Radiation Therapy for Upfront Treatment of Patients with Newly-Diagnosed
Glioblastoma Multiforme: Safety and Efficacy Assessment
https://www.ncbi.nlm.nih.gov/pubmed/29722661
"Bortezomib is given intravenously/subcutaneously at 1.3 mg/ m² on days 1, 4, 8, 11, 29, 32, 36, and 39 during radiation as early as 14 days after surgery. Temozolomide is given daily (75mg/m2) during radiation, followed by 5 days out of 28 with a dosage of 150-200 mg/m2, for up to 24 cycles. Bortezomib at 1.3 mg/m2 is given on days 1, 4, 8, and 11 of each subsequent 28 day cycle. Both bortezomib and temozolomide will continue until progression or up to 24 cycles.
Bortezomib was initially given via intravenous (IV) infusion, but the protocol was later modified to subcutaneous (SC) injection at ~10 months after the first patient had begun treatment (e.g., August 2012), due to the reported similar efficacy with improved safety profile (11, 12).
Our data were encouraging for newly diagnosed GBM when bortezomib was combined with radiation therapy and temozolomide. In preclinical models, bortezomib has been shown to be a radiosensitizer. That could be one of the reasons for lacking of efficacy in the treatment of recurrent GBM with bortezomib and vorinostat (a histone deacetylase inhibitor) when radiotherapy was not used."
It is unclear, however, what effect on the duration of survival was provided by the treatment after the recurrence:
"Among all 24 patients, 3 had no progression at the time of the last follow-up and 1 lost followup. The remaining 20 patients had documented recurrence. The treatments for recurrence were at attending physician’s discretion. For first recurrence, 4 patients were treated with temozolomide re-challenge, 9 with bevacizumab single agent, 4 with bevacizumab plus lomustine (CCNU), 1 with bevacizumab plus onartuzumab, 1 with bevacizumab plus pembrolizumab, and 1 with nivolumab. For further tumor progression, treatment therapies consisted of traditional chemotherapy agents (CCNU, carboplatin or etoposide) with and without bevacizumab. Four patients received stereotactic radiation therapy during further recurrences."
Failed tests or without any outstanding result:
A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/26285768
A minimum of 4 weeks after radiation and full recovery after surgery were required.
Each cycle of therapy consisted of 6 weeks of oral tamoxifen 120 mg twice daily and intravenous bortezomib 1.3 mg/m2 on days 3, 6, 10, 13, 24, 27, 31, and 34 of every 6-week cycle.
A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/27300524
All patients received bortezomib 1.7 mg/m2 intravenously (IV) on day 1, 4 and 8. Patients underwent surgical resection of their tumor on day 8 or 9. Patients started TMZ 75 mg/m2 orally on days 1–7 and 14–21 and bortezomib 1.7 mg/m2 IV on days 7 and 21. Each post surgery cycle was 4 weeks.
Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma
https://www.ncbi.nlm.nih.gov/pubmed/27502784
The three agents were administered in 42 day cycles as shown in Fig. 1. Bortezomib was given at 1.3 mg/m2 on day 1 of weeks 1–4. Bevacizumab was given at a dose of 10 mg/kg on day 1 of weeks 1, 3, and 5. Temozolomide was given at doses of 25 mg/m2 (Group 1), 50 mg/m2 (Group 2), or 75 mg/m2 (Group 3) on days 1–28 of each cycle.
___________________________
I was also interested in this article, where it was concluded that "combination of bortezomib and autophagy inhibitors may shed new light on glioblastoma treatment."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840293/
The open question remains about the use of bortezomib in a cocktail for MGMT-methylated patients only after radiotherapy.
Nice analysis, but my question would be if it was primarily acting as a radiosensitizer why did it not improve outcomes for MGMT unmethylated patients, because MGMT is only involved in repairing damage from alkylating chemotherapy agents rather than radiation. Outcomes for the 13 MGMT unmethylated patients were no better than what would be expected with standard treatments alone.
ReplyDeleteThe results are surprising, and I haven't been able to draw any conclusions. Many phase 1 trials based on a small number of patients (10 or less) have not looked so promising when tested on a larger number of patients.
In the group of 10 MGMT-methylated patients, even the median PFS of 24.7 months is surprisingly long, and this statistic is of course was not affected by any follow-up treatments at recurrence.
The authors of the study «Phase II Study of Bortezomib in Combination with Temozolomide and Regional Radiation Therapy» write that «In preclinical models, bortezomib has been shown to be a radiosensitizer. That could be one of the reasons for lacking of efficacy in the treatment of recurrent GBM with bortezomib and vorinostat (a histone deacetylase inhibitor) when radiotherapy was not used.»
ReplyDeleteI read this study:
Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266383/
«Vorinostat was administered at a dose of 400 mg daily for 14 days of a 21-day cycle, and bortezomib was administered at a dose of 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 of the cycle.
… The trial was closed at the predetermined interim analysis, with 0 of 34 patients being progression-free at 6 months.»
Again in this failed study, bortezomib was administered intravenously.
In these two studies, the conclusion was made that there is an equal effect of intravenous and subcutaneous bortezomide administration and a safer subcutaneous injection profile:
https://www.ncbi.nlm.nih.gov/pubmed/21507715
https://www.ncbi.nlm.nih.gov/pubmed/23018466
Thus, apparently, the difference in the mode of administration did not matter, since also in a successful study the first 10 months of bortezomide was administered intravenously.
Perhaps the difference between failing studies and successful with fantastic results - in doses and schedule of Temozolomide?
https://www.ncbi.nlm.nih.gov/pubmed/23645448
"In this study we investigated the effect of sequential treatment with BZ and TMZ on cell proliferation-viability and apoptosis of the human T98G and U87 GBM cell lines.
… proteasome inhibition by BZ overcomes MGMT-mediated GBM chemoresistance, with scheduling of administration being critical for obtaining the maximal tumoricidal effect of combination with TMZ."
In a successful study, Temozolomide was administered at doses of 15-200 mg / m2. No other study had such doses of Temozolomide.
This comment has been removed by the author.
ReplyDeleteI am still surprised by the incredible results of a successful study with Bortezomib: https://www.ncbi.nlm.nih.gov/pubmed/29722661
ReplyDeleteVery strange, but I have not seen any more successful results with any other kind of treatment! Now I'm studying the possibility of using bortezomib in my case (after radiotherapy and with a residual tumor).
I also found this study:
"Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma"
https://clinicaltrials.gov/ct2/show/results/NCT00611325
The results, however, again were not encouraging:
Avastin was administered intravenously at a dose of 15 mg / kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7-2.5 mg / m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Median Overall Survival (OS): 8 months (Patients taking enzyme-inducing anti-epileptic drugs) and 6 months (Patients not taking enzyme-inducing anti-epileptic drugs).
An interesting new article, but it is very difficult to draw any practical conclusions:
ReplyDelete"An intrinsic metabolic clock continues to function in proliferating cells, controlling diverse metabolisms and highlighting differential states of tumor suitability for more efficient, time-dependent chemotherapy when the redox state is high and GPL metabolism low."
"The proteasome inhibitor bortezomib was shown to promote ROS generation in mitochondria of different cancer cells and ultimately to cause apoptosis [51]; these observations further support our results showing that the highest cell susceptibility to bortezomib treatment was found when the peak in ROS was attained."
https://www.ncbi.nlm.nih.gov/pubmed/29881948
http://sci-hub.tw/https://doi.org/10.1007/s12035-018-1152-3
Description of the role of bortezomib in a new clinical trial: https://clinicaltrials.gov/ct2/show/NCT03643549
ReplyDelete"Patients harbouring tumours with functional O6 methylguanine DNA methyltransferase (MGMT) DNA repair enzyme efficiently repair the DNA damage inflicted by Temozolomide and gain limited benefit from this chemotherapy. Bortezomib depletes the MGMT enzyme, restoring the tumour´s susceptibility to Temozolomide, if the chemotherapy is administered in the precise schedule when the MGMT enzyme is depleted. Additionally, Bortezomib inhibits the growth of tumour cells by blocking autophagy flux. Temozolomide causes genotoxic stress in cancer cells that in turn respond by inducing protective processes such as autophagy. If both autophagy and MGMT DNA repair enzyme are blocked a priori, the efficacy of Temozolomide will be enhanced. Thus, pre-treating the tumour with Bortezomib prior to administration of Temozolomide leads to DNA repair enzyme depletion and blockade of autophagy-induced survival signals. The combined effect will sensitize the tumour to therapy, improve chemotherapy efficacy and prolong patient survival outcomes.
Hypothesis: Pretreatment with Bortezomib administered prior to Temozolomide will sensitize recurrent GBM with unmethylated MGMT promoter to standard TMZ in palliative setting."
All of this only matters if bortezomib can actually cross the blood-tumor barrier into the tumor in therapeutic concentrations. This has never been demonstrated. This is probably one of the main reasons most targeted agents have failed in brain tumors - the drugs aren't reaching the target tissue in sufficient concentrations.
DeleteIf bortezomib was acting as an MGMT inhibitor, it should be more, not less effective for MGMT unmethylated GBM. Whereas in this trial it was seeminly more effective in the MGMT methylated group https://www.ncbi.nlm.nih.gov/pubmed/29722661
I'm still skeptical about bortezomib for brain tumors, but would be happily surprised if some future trial confirmed its usefulness. The long PFS of the 10 MGMT-methylated patients in the trial discussed in the original post of this thread should prompt larger studies, but given the negative results of all other trials of bortezomib for GBM, the jury is still out.