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Property "Has original text" (as page type) with input value "The most notable development in drug combinations has been the addition of the anti- angiogenic drug, Avastin (also known as bevacizumab), to the standard Stupp protocol. As will be discussed later, 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 gold standard Temodar protocol.
Recently, there have been two large randomized phase III clinical trials comparing
the Stupp protocol and the Stupp protocol + Avastin, for newly diagnosed patients. In the first of these (70), known as the AVAglio trial, median PFS was 10.6 months for those receiving Avastin versus 6.2 months for those receiving only the Stupp protocol, a statistically significant difference. However, median overall survival was not different (16.8 months vs. 16.7 months). It should be noted that patients in the control group
typically received Avastin after tumor progression occurred, so that the comparison was
really between Avastin given early versus Avastin given only after recurrence. Additional results were that 72% of the Avastin group was alive at one year, compared to 66% of the control group, while two year survival was 34% vs. 30%.
In the second of these large trials (71), conducted by the RTOG consortium, the design was essentially similar to the AVAglio trial, as were the results. Median PFS was 10 months for those receiving Avastin vs. 7.3 months for the control group (again statistically significant), while median overall survival was 15.7 months for the Avastin group compared to 16.1 months for the control, a nonsignificant 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 the initial treatment. However, there is no benefit for overall survival, when compared to withholding Avastin until recurrence is detected. An additional feature of the results, not emphasized by the authors of the reports, is that the overall survival times were not notably better, and in many cases worse, than those obtained when the Stupp protocol is combined with various other treatment agents." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has Usefulness Explanation" (as page type) with input value "* Immune System Enhancement: Augmentation of T-helper cell activity, crucial for targeting cancer cells.
- Inhibition of Angiogenesis: Reduction in blood vessel formation essential for tumor growth.
- Direct Cytotoxic Effects: Induction of apoptosis in cancer cells, including glioblastoma.
- Reduction of Chemotherapy Toxicity: Mitigation of chemotherapy side effects, improving tolerability and adherence to treatment schedules.
- Modulation of Tumor Metabolism: Affects energy production pathways in cancer cells, making them more susceptible to treatments." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "Accutane (isotretinoin, 13-cis retinoic acid)
When Temodar has been combined with accutane, a retinoid used for acne treatment (also known as 13-cis-retinoic acid, or isotretinoin), the PFS-6 (for recurrent tumors improved from the 21% historical value of Temodar alone, to 32% (96).
In contrast to the improvement in clinical outcome when accutane was combined with Temodar for recurrent tumors, a clinical trial with newly diagnosed patients that combined Temodar with accutane produced less impressive results (97). Fifty-five evaluable patients used both accutane and low-dosage Temodar during radiation, followed by full-dose Temodar + accutane, and produced a median survival time of only 57 weeks and a two-year survival of 20%, both below the survival rates from the large clinical trial with the same protocol that used Temodar without accutane. A second, retrospective clinical trial in Canada (98) that combined accutane with Temodar with newly diagnosed patients produced a median survival of 15.1 months and a two-year survival of 26.7%, both comparable to when Temodar has been used alone.
Although accutane appears not to improve outcome when added to the standard Temodar protocol, it does seem to have activity as a single agent. A phase II clinical trial
evaluating accutane for recurrent gliomas was conducted at the M. D. Anderson Brain Tumor Center (99). The median survival time was 58 weeks for glioblastoma patients and 34 weeks for grade III gliomas. Aggregated over both tumor types (43 evaluable patients) 3 achieved a partial tumor regression, 7 had minor regressions, and 13 had tumor stabilization. A more complete report, using accutane with 86 glioblastoma patients with recurrent tumors was less impressive (100). Median survival time from the onset of treatment was 25 weeks and PFS-6 was 19%. Accutane now is used at M. D. Anderson as a "maintenance therapy" for patients after initial treatment with radiation or traditional chemotherapy. It also has been used in Germany for patients who have had a complete response to other treatment modalities as a maintenance therapy (101). The major side effects have been dry skin, cracked lips, and headaches, although occasional liver toxicity has also occurred. Increases in blood lipid levels frequently occur, often requiring anti- cholesterol medication such as Lipitor. Accutane also may produce severe birth defects if taken during pregnancy.
Although various data now suggest that accutane should not be combined with chemotherapy (for example, see the discussion below in this chapter entitled A trial of 3 repurposed drugs plus Temodar), a series of studies with various types of cancer, including pancreatic, ovarian, colorectal, and melanoma (although not yet with brain tumors), suggest it can be very effective for patients who get a good response from their initial treatment protocol. This is especially relevant to GBM patients who have clean MRIs either after surgery or after treatment with radiation and chemotherapy. An example of the protocol with ovarian cancer involved 65 patients who received the standard treatment of a taxane and a platinum drug (316). After one year of the standard treatment those receiving a benefit were moved to a maintenance treatment using subcutaneous low-dose IL-2 plus oral 13 cRA at a dose of 0.5 mg/kg. This plan was continued for one year after which frequency of dosing was gradually reduced. Patients receiving this treatment plan had a median PFS of 23 months and a median survival of 53 months. Concomitantly, various measures of immune function (lymphocyte count, NK cell count) were substantially improved and there was a substantial reduction in the level of VEGF, reflecting a reduction in angiogenesis." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "Angiotensin-II is a peptide hormone produced from angiotensin-I by the action of angiotensin converting enzyme (ACE). The main effect of angiotensin-II is vasoconstriction and a resulting increase in blood pressure. Therefore ACE inhibitors and angiotensin-II receptor blockers are used as anti-hypertensive drugs, especially in heart disease. More recently these drugs have been repurposed for use in cancer studies.
A retrospective study published in 2012 (328) examined the steroid-sparing effects of angiotensin-II inhibitors, incuding ACE inhibitors and angiotensin-II receptor blockers (ARBs). Of a total cohort of 87 newly diagnosed glioblastoma patients, 29 patients were identified who were treated prior to radiation for high blood pressure. 18 of these were treated with either ACE inhibitors (n=3) or angiotensin-II receptor blockers (n=15). Although no survival benefit with angiotensin-II inhibitors was observed in this study, the 18 patients treated with an angiotensin-II inhibitor required half the steroid dose compared to all other patients in the study (mean prednisolone dose of 29 mg per day versus 60 mg per day), and this difference remained significant in multivariate analysis (p=0.003).
A later retrospective study by the same group published in January 2016 (329) focused specifically on the angiotensin-II receptor blocker class of drugs and their effects on vasogenic edema in glioblastoma patients. In this study, 11 patients taking angiotensin-II receptor blockers (ARBs) for hypertension were compared with 11 matched patients with similar age, tumor size, and tumor location, but not taking medication for hypertension. There was a significant 66% reduction in the FLAIR ratio in the patients taking ARBs compared to the matched patients not taking ARBs. As FLAIR signal can represent either tumor infiltration or vasogenic edema, the nature of the peri-tumoral FLAIR signal was assessed with apparent diffusion coeffient (ADC) mapping. Nine evaluable patients taking 28
ARBs had a 34% reduction in ADC ratios compared to their matched controls not taking ARBs, confirming the ability of this class of drugs to reduce peri-tumoral edema.
A 2015 study, also by the group in France, suggests angiotensin-II inhibitors (including ACE inhibitors and ARBs) may also lead to superior survival outcomes (330). In this study, 81 GBM patients were included. Seven of these patients were taking ACE inhibitors and 19 were taking ARBs for hypertension. The 26 patients using angiotensin-II inhibitors had increased progression-free and overall survival (8.7 and 16.7 months) compared to the patients not taking these drugs (7.2 and 12.9 months). Use of angiotensin-II inhibitors was a significant positive prognostic factor for both PFS and OS in multivariate analysis.
A randomized phase 3 trial in France (NCT01805453) has recently completed recruitment, and is testing the influence of losartan (an ARB) versus placebo on the steroid dose required to control edema on the last day of radiotherapy. Another drug in this class, telmisartan, has superior penetration into the central nervous system (331) and may therefore be a better choice.
See Chapter 13 for a discussion of Angiotensin system inhibitors plus Avastin" contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "Chloroquine and Hydroxychloroquine
In a series of studies conducted in Mexico City (23, 24, 25) patients received the traditional chemotherapy agent BCNU, with or without a 150 mg daily dose of chloroquine (the equivalent of 250 mg chloroquine phosphate). The results were that patients receiving chloroquine had a median survival time of 25-33 months, while those receiving BCNU alone had a median survival time of 11 months. Chloroquine at the dose used had no detectable toxicity. Because the cytotoxic mechanism of BCNU is similar to that of Temodar, it seems likely that chloroquine should increase the efficacy of Temodar, although this has yet to be demonstrated. One of several mechanisms by which chloroquine makes chemotherapy more effective is that it inhibits autophagy, an intracellular process that involves the cell digesting some of its internal parts to allow repair of the damage caused by the chemotherapy.
Disappointingly, a multi-center phase I/II trial testing the addition of7hydroxychloroquine (which differs from chloroquine only by a single hydroxyl group) to standard radiochemotherapy for newly diagnosed glioblastoma failed to show any improvement in survival over historical averages. In the phase I safety and toxicity study, all 3 subjects given 800 mg/d hydroxychloroquine along with chemoradiation experienced grade 3 or 4 neutropenia or thrombocytopenia, and 600 mg/d was determined to be the maximum tolerated dose. 76 patients were then treated at this dose in the phase 2 cohort. Autophagy inhibition (the proposed mechanism of action) was not consistently achieved at that dose, and patient survival (median OS 15.6 months, 2-year survival of 25%) was not improved relative to historical control groups. The study concluded that hydroxychloroquine was ineffective in this context at the maximum tolerated dose (304).
Recent preclinical work (305) has shown increased reliance on autophagy and sensitivity
to chloroquine treatment in EGFR-overexpressing glioma cells, and any future trials with chloroquine for high-grade gliomas may benefit from a subgroup analysis based on EGFR status." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "Based on observations of the relationship between hypothyroid status (depressed thyroid function) and improved outcomes in cancer patients dating at least back to 1988, Aleck Hercbergs and colleagues at the Cleveland Clinic conducted a clinical trial, published in 2003, in which 22 high grade glioma patients were treated with propylthiouracil to induce chemical hypothyroidism, and high dose tamoxifen (349). 15 of the patients had the diagnosis of glioblastoma and the remainder were grade 3 gliomas. Half of the patients (11 of 22) attained hypothyroid status, although no clinical symptoms of hypothyroidism were observed. A survival analysis determined that median survival in the 11 hypothyroid patients was 10.1 months, while median survival in the non-hypothyroid group was only 3.1months. After adjusting for the younger age of the hypothyroid patients, survival was still longer in the hypothyroid group, with borderline statistical significance (p=0.08).
Later, in 2005, the discovery of cell surface receptors for thyroid hormones on avB3 (alphaVbeta3) integrins, provided a mechanism for their cancer-promoting effects (350). This particular integrin tends to be overexpressed on cancer cells, and stimulation of this integrin by thyroid hormones leads to increased angiogenesis, tumor cell proliferation, and resistance to apoptosis (351).
Following publication of the 2003 trial, many cancer physicians and cancer patients reached out to Hercbergs, resulting in a cohort of 23 advanced cancer patients treated informally with thyroid suppression therapy in addition to standard treatments (351). Patients who were taking synthetic T4 for pre-existing hypothyroidism were abruptly switched to synthetic T3 (Cytomel) and in three of these patients there was a rapid and durable tumor remission observed in conjuction with standard treatments. In the remaining patients, methimazole was used to depress T4 levels to below the reference range, and patients again received synthetic T3 hormone (Cytomel). The rationale for this 31
is that even though T3 is the active form of thyroid hormone, the affinity for T4 at the thyroid hormone receptor on the integrin is greater than for T3, and T4 is a stronger inducer of cancer cell proliferation. The suppression of T4 and supplementation with T3 (Cytomel) is therefore thought to reduce the major cancer-promoting effect of thyroid hormones while avoiding the clinical symptoms of hypothyroidism, such as fatigue.
Four patients with glioblastoma were included in this study, including a 67 year old male with a KPS of 70 and a partial resection who survived 36 months (3 years), and a 64 year old male with a KPS of 60 who had undergone a biopsy only and lived for 48 months (4 years). Both of these patients had an expected survival of 10 months. A third female glioblastoma patient, aged 68, had a low KPS of 40 and survived for 8 months.
Several patients were excluded from the study who had either failed to achieve free T4 depletion, or who voluntary discontinued treatment (perhaps due to a perception of lack of benefit or an actual lack of benefit). Therefore the 100% response rate observed in this study is perhaps an exaggeration, although the long survival of two out of four advanced GBM patients certainly suggests an effect of the treatment, as standard treatments alone rarely lead to such positive outcomes. Additionally, Hercbergs et al. published a case report of a 64 year old patient with optic pathway glioma, progressive after standard treatments, who responded to T4 depletion with propylthiouracil followed by carboplatin chemotherapy with a remission period of 2.5 years and overall survival of 4.5 years (352).
A phase 2 clinical trial testing T4 suppression with methimazole and Cytomel (synthetic T3) in addition to standard treatment for newly diagnosed glioblastoma has started recruiting in Tel-Aviv, Israel early in 2016 (NCT02654041)." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "This is a naturally occurring hormone secreted by the pineal gland that regulates the body's diurnal rhythm. It is commonly used for the treatment of jet lag and for insomnia. It is readily available in any health food store and most drug stores. Its role in cancer treatment has been based on the assumption that it boosts the immune system, with the current hypothesis being that it augments the activity of T-helper cells. It recently also has been shown to inhibit angiogenesis (225). It may also have direct cytotoxic effects on some types of cancer cells, notably melanoma cells. It has no known toxic side effects.
Clinical research on the use of melatonin for cancer treatment has been done primarily in Italy, where it has been used either as a single agent after radiation treatments, or in combination with various chemotherapy or immunotherapy regimens, most frequently interleukin-2. Part of the rationale for such combinations is that it decreases the side effects of the chemotherapy, especially with respect to blood counts. One of the clinical 32
studies (226) randomly assigned 30 GBM patients either to radiation alone (n=16) or to radiation concomitant with 20 mg/day of melatonin (n=14). Melatonin was continued after completion of the radiation. Survival was significantly greater for subjects receiving the melatonin. In terms of one-year survival rates, 6/14 patients receiving melatonin were alive, while only 1/16 patients without melatonin was alive.
This GBM study involved a relatively small number of patients, so that the effects should be considered tentative until a larger study is conducted. However, comparable effects have been reported in a similar design for the use of melatonin with advanced lung cancer (227). Like the GBM study, a substantial increase in survival rate occurred for the patients receiving melatonin.
To date there have been at least a dozen phase-2 clinical trials using melatonin either alone or in combination with other agents and five phase-3 trials involving random assignment of subjects to melatonin versus some type of control group. The majority of these has been relatively small and has involved patients in the terminal stages of their disease, which is perhaps why American oncologists have largely ignored them.
However, some trials have been much larger and seem to leave little doubt that melatonin significantly increases the efficacy of chemotherapy. One of the most extensive randomized clinical trials involved 250 patients with advanced metastatic cancer of various types (228). Patients were randomly assigned to chemotherapy alone (using different chemotherapies for different types of cancer) or chemotherapy plus 20 mg of melatonin per day. Objective tumor regression occurred in 42 (including 6 complete regressions) of 124 patients receiving melatonin but in only 19/126 (with zero complete regressions) of the control patients. A comparable difference occurred for survival rate: 63/124 of those receiving melatonin were alive after one year while only 29/126 were alive of those receiving chemotherapy alone. A different trial, involving 100 patients with metastatic non small-cell lung cancer (229), compared chemotherapy alone with chemotherapy in combination with melatonin. With chemotherapy alone, 9 of 51 patients had a partial tumor regression, while 17 of 49 chemo + melatonin patients had either a complete (n=2) or partial (n=15) regression. Twenty percent of the chemo-alone patients survived for one year and zero for two years, while the corresponding numbers for chemo + melatonin were 40% and 30%. Melatonin not only increased the efficacy of chemotherapy, but also significantly reduced its toxicity.
The most extensive report included 370 patients, subdivided into three different types of cancer: lung cancer (non-small cell), colorectal cancer, and gastric cancer (230). Aggregated over all three types, the response rate (percentage of patients with tumor regression) was 36% for those treated with chemotherapy and melatonin, versus 20% for those treated with chemotherapy alone. The corresponding two-year survival rates were 25% vs. 13%. Melatonin’s benefits occurred for all three cancer types that were included. Moreover, patients receiving melatonin had fewer side effects. 33
These trials leave little doubt that the effects of melatonin are of clinical significance. Moreover, a recent study has shown that using multiple components of the pineal gland secretions instead of melatonin alone enhances clinical effectiveness still further (231). One caveat about the use of melatonin is that a recent randomized trial compared radiation treatment for metastatic brain cancer with and without melatonin and found no benefit of the melatonin (232). Given that almost all of the supporting evidence for the use of melatonin has come from its addition to chemotherapy, it is possible that it offers no benefit when added to radiation, perhaps because of its strong antioxidant properties." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "Resveratrol
This compound, commonly associated with red wine, has gained attention for its health benefits, including potential anti-cancer properties. It affects mechanisms like the inhibition of NF-kB and the activation of sirtuins that contribute to its anti-aging and anti-inflammatory effects. Although promising, its clinical efficacy in cancer treatment requires further validation.
Resveratrol's anti-cancer potential was highlighted in several studies where it was shown to modulate hormone receptor signaling pathways, making it of interest in hormone-driven cancers such as breast and prostate cancer. Like many supplements, its bioavailability is a concern, but ongoing research is addressing these challenges with novel delivery systems." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "One disadvantage of the DCVax approach is that it requires that brain tissue be extracted from individual patients in order to make the vaccine. An alternative approach has been used by Dr. Black’s team at Cedars Sinai. Dendritic cells are still drawn from the peripheral blood of individual patients, but instead of tumor tissue lysate being mixed with those cells, a collection of six proteins typical of of GBMs is mixed with the
dendritic cells, creating an immune response to those antigens, with the mixture then returned to the patient via vaccinations. In a phase I trial (158), 20 GBM patients (17 newly diagnosed, 3 with recurrent tumors) received three vaccinations two weeks apart. Median PFS was 16.9 months, and median overall survival was 38 months. At the time of the clinical trial report, six of the patients had shown no sign of tumor recurrence. A later follow-up was reported in a Press release from ImmunoCellular Therapeutics (159), the biotech company sponsoring the vaccine (now called ICT-107). Survival rate at three years was 55%, with 38% of patients showing no evidence of recurrence, The most
recent update of the clinical trial (160), presented at the 2013 meeting of the World Federation of Neuro-oncology, reported that 7 of the original 16 patients in the trial were still alive, with survivals ranging from 60 to 83 months. One additional patient who was still tumor free after five years died from leukemia.
Currently ongoing is a randomized phase II trial, the interim results of which have recently reported by ImmunoCellular Therapeutics (161). Despite the impressive results described above, there was no statistically significant difference in median survival between the vaccine group and those treated with a placebo, although there was a numerical 2-3 month advantage for the vaccine group. However there was a similar difference in progression-free survival, which was statistically significant. The company emphasized that the results were preliminary and that they expected the difference in progression-free survival to translate into differences in overall survival with longer follow-up. However, the results also suggest that median survival and percentage of long-term survivors may be only weakly correlated due to the possibility that only a minority of patients benefit from the treatment, but those who do benefit a great deal.
Updated data from the phase II ICT-107 trial were presented on June 1, 2014 at the annual ASCO meeting (309). An important conclusion to be drawn from the new data is that mainly patients positive for HLA-A2 (a variant of the Human Leukocyte Antigen-A gene) seem to derive significant benefit from the vaccine. HLA are antigen-presenting proteins found at the cell surface. HLA-A2 is the most common variant in North America and Europe according to the press release and this group comprised 62% of patients randomized in this trial. The updated results are presented only for HLA-A2 positive patients, with results further subgrouped according to MGMT methylation status. Survival results in this trial are measured from the time of randomization after chemoradiation, and average time from initial surgery to randomization was 83 days (2.7 months).
For HLA-A2 positive patients with unmethylated MGMT, the ICT-107-vaccinated group had a median 4-month survival advantage compared with the placebo-vaccinated group. The ICT-107 group also had a median 4.5 month advantage in progression-free survival. These advantages in the vaccine-treated group did not reach statistical significance, though that is perhaps due to the small numbers of patients within these subgroups. 21% of ICT-107 treated patients were still alive at the time of the analysis, compared with only 7% of the placebo-treated patients.
Median survival has not yet been reached in the HLA-A2 positive, MGMT methylated group, though in this subgroup, ICT-107 treatment led to a dramatic and statistically significant increase in median progression-free survival: 24.1 months versus 8.5 months in the placebo-treated group. It is likely that this huge improvement in median progression-free survival in this subgroup will translate into significant median overall survival improvement.
Sadly, in June 2017, Immunocellular Therapeutics announced that their phase 3 ICT-107 trial was suspending recruitment due to insufficient funding. In the press release it was stated the company was looking for a partner for collaboration or acquisition of its ICT-107 program, and they were also taking steps to ensure the continued follow up of patients already being treated in the trial." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Property "Has original text" (as page type) with input value "In aseries of studies conducted in Mexico City (23, 24, 25) patients received the traditional chemotherapy agent BCNU, with or without a 150 mg daily dose of chloroquine (the equivalent of 250 mg chloroquine phosphate). The results were that patients receiving chloroquine had a median survival time of 25-33 months, while those receiving BCNU alone had a median survival time of 11 months. Chloroquine at the dose used had no detectable toxicity. Because the cytotoxic mechanism of BCNU is similar to that of Temodar, it seems likely that chloroquine should increase the efficacy of Temodar, although this has yet to be demonstrated. One of several mechanisms by which chloroquine makes chemotherapy more effective is that it inhibits autophagy, an intracellular process that involves the cell digesting some of its internal parts to allow repair of the damage caused by the chemotherapy.
Disappointingly, a multi-center phase I\/II trial testing the addition of7hydroxychloroquine (which differs from chloroquine only by a single hydroxyl group) to standard radiochemotherapy for newly diagnosed glioblastoma failed to show any improvement in survival over historical averages. In the phase I safety and toxicity study, all 3 subjects given 800 mg\/d hydroxychloroquine along with chemoradiation experienced grade 3 or 4 neutropenia or thrombocytopenia, and 600 mg\/d was determined to be the maximum tolerated dose. 76 patients were then treated at this dose in the phase 2 cohort. Autophagy inhibition (the proposed mechanism of action) was not consistently achieved at that dose, and patient survival (median OS 15.6 months, 2-year survival of 25%) was not improved relative to historical control groups. The study concluded that hydroxychloroquine was ineffective in this context at the maximum tolerated dose (304).
Recent preclinical work (305) has shown increased reliance on autophagy and sensitivity
to chloroquine treatment in EGFR-overexpressing glioma cells, and any future trials with chloroquine for high-grade gliomas may benefit from a subgroup analysis based on EGFR status. traditional chemotherapy agent BCNU, with or without a 150 mg daily dose of chloroquine (the equivalent of 250 mg chloroquine phosphate). The results were that patients receiving chloroquine had a median survival time of 25-33 months, while those receiving BCNU alone had a median survival time of 11 months. Chloroquine at the dose used had no detectable toxicity. Because the cytotoxic mechanism of BCNU is similar to that of Temodar, it seems likely that chloroquine should increase the efficacy of Temodar, although this has yet to be demonstrated. One of several mechanisms by which chloroquine makes chemotherapy more effective is that it inhibits autophagy, an intracellular process that involves the cell digesting some of its internal parts to allow repair of the damage caused by the chemotherapy.
Disappointingly, a multi-center phase I\/II trial testing the addition of7hydroxychloroquine (which differs from chloroquine only by a single hydroxyl group) to standard radiochemotherapy for newly diagnosed glioblastoma failed to show any improvement in survival over historical averages. In the phase I safety and toxicity study, all 3 subjects given 800 mg\/d hydroxychloroquine along with chemoradiation experienced grade 3 or 4 neutropenia or thrombocytopenia, and 600 mg\/d was determined to be the maximum tolerated dose. 76 patients were then treated at this dose in the phase 2 cohort. Autophagy inhibition (the proposed mechanism of action) was not consistently achieved at that dose, and patient survival (median OS 15.6 months, 2-year survival of 25%) was not improved relative to historical control groups. The study concluded that hydroxychloroquine was ineffective in this context at the maximum tolerated dose (304).
Recent preclinical work (305) has shown increased reliance on autophagy and sensitivity
to chloroquine treatment in EGFR-overexpressing glioma cells, and any future trials with chloroquine for high-grade gliomas may benefit from a subgroup analysis based on EGFR status." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
