Introduction
Chemotherapy has a crucial role in the management of gliomas. Traditionally, the management is characterized by an extensive surgery followed by a combination of radiotherapy (RT) and chemotherapy. In general, chemotherapy has been used as a neoadjuvant, adjuvant, or concurrent treatment, and our understanding of optimal use has continued to evolve over time. Neoadjuvant chemotherapy is administered prior to the main or definitive treatment, which is usually surgery (i.e., before surgery). Adjuvant chemotherapy is administered after the main or definitive treatment. For brain or spinal cord tumors, this is typically after radiation therapy (i.e., adjuvant to radiation). In some cases, concurrent chemotherapy may be administered simultaneously with radiation therapy. Different chemotherapeutic regimens have been investigated in both low-grade gliomas (LGGs) and high-grade gliomas (HGGs). Overall, the impact of chemotherapy for disease control still remains modest as compared with surgery or RT. New compounds are needed, and searching for novel druggable pathways is the current mission of basic and translational research in neuro-oncology.
Chemotherapy regimens
Here, we describe the traditional chemotherapeutic schedules used in daily clinical practice according to the results from the most important clinical trials in both LGGs and HGGs. First, we review common chemotherapy regimens used in clinical practice. Then, we present a series of cases and summarize the landmark clinical trials that inform the use of chemotherapy in patient management.
Temozolomide
Temozolomide (TMZ) is an oral agent converted by the liver to the active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The antineoplastic effect results from alkylating the middle guanine residue of DNA, leading to defective mismatch repair and cell death. TMZ is used commonly in many central nervous system (CNS) regimens due to its many favorable characteristics including good oral bioavailability, limited protein binding, and good CNS penetration with measurable levels being achieved in the cerebrospinal fluid (CSF) and in brain parenchyma following oral administration. Considering these properties, TMZ may be used with different schedules and timing for treating many gliomas, CNS lymphoma, or selected brain or leptomeningeal metastases.
Treatment Schedules . TMZ is often administered concurrently and/or adjuvant to radiation therapy.
Concurrent Temozolomide. The most frequent regimen consists of TMZ administered at 75 mg/m 2 per day for 6 consecutive weeks along with conformal RT according to the Stupp regimen. , The aim of this treatment is to increase in a synergistic way the effect of combined radiation and chemotherapy with acceptable tolerability, possibly as a result of a radiosensitizing effect of TMZ during radiation. Several trials have demonstrated a significant benefit of TMZ in newly diagnosed glioblastoma (GBM). Thus, chemoradiation represents the standard of care (SOC) for GBM in clinical practice and the main control arm in clinical trials with experimental drugs.
Adjuvant Temozolomide. TMZ may also be administered adjuvantly or in the recurrent setting. Several different schedules may be employed. The most frequent schedule following chemoradiation consists of 150–200 mg/m 2 per day for day 1–5 every 28 days for six cycles. Cycle 1 is administered at 150 mg/m 2 per day and, if there is no unacceptable toxicity, this is escalated to 200 mg/m 2 per day for the remaining cycles. The O-6-methylguanine-DNA methyltransferase (MGMT) gene plays an important role in the clinical response to TMZ. The MGMT enzyme is involved in repairing DNA following alkylating-induced damage such as those caused by TMZ. As a result, silencing of this gene (e.g., through methylation of the MGMT promoter) limits the cancer cells ability to survive TMZ-induced DNA damage and is associated with improved responses. Methylation of the MGMT promoter is associated with a better overall survival (OS) in newly diagnosed GBM. Clinical trials have also studied the use of “intensified” protocols to increase the total dose of TMZ delivered, deplete the amount of MGMT in the cell, and overcome treatment resistance. , These dose-dense regimens include schedules such as 75–100 mg/m 2 per day for 3 weeks-on and 1 week-off, or 120–150 mg/m 2 per day for 1 week-on and 1 week-off, or “continuous” administration at 50 mg/m 2 per day for 28-out-of-28 days (e.g., metronomic). These schedules did not show improvement in OS as compared with standard schedules with a major risk of toxicity (see Case 4.4 : Newly diagnosed glioblastoma, later).
Other Temozolomide Regimens. Other regimens have also been studied. TMZ has been investigated in the neoadjuvant setting (before conformal RT) in both grade III astrocytomas and GBM. There was no advantage in OS in GBM. Neoadjuvant TMZ in grade III astrocytoma resulted in a longer survival at 5 years. Preoperative TMZ in LGGs has also been suggested in order to decrease the tumor volume, amount of tumor infiltration, and facilitate a safer, more radical resection.
Toxicity. In general, TMZ is well tolerated by most patients. The most frequent side effects are nausea/vomiting and fatigue. However, approximately 20% of patients discontinue TMZ due to myelosuppression, in particular for thrombocytopenia (<100,000/mm 3 ). Severe thrombocytopenia as defined by the common terminology criteria for adverse events (CTCAE) as grades 3 or 4 and prolonged thrombocytopenia occurs in about 5% of patients. Moreover, a rare idiosyncratic reaction may appear during chemoradiation with a severe decrease of red blood cells (<2 × 10 6 /mm 3 ), hemoglobin (<8.0 g/dL), thrombocytes (<75,000/mm 3 ), and febrile neutropenia (<1,000/mm 3 ).
PCV chemotherapy: procarbazine, CCNU, and vincristine
Procarbazine (PC), lomustine (CCNU), and vincristine is a combined therapy administered in a 6-week cycle with CCNU on day 1, vincristine on days 8 and 29, and PC on days 8–21.
PC is an oral alkylating drug with modest efficacy in HGGs when used as monotherapy. Fatigue, anorexia, and myelosuppression are the most frequent adverse events. Patients must follow a tyramine-free diet to avoid an excess tyramine catecholamine reaction.
CCNU is an oral nitrosourea that is also the standard second-line chemotherapy in progressive HGGs in Europe. Toxicity includes cumulative myelosuppression, nausea/vomiting, fatigue, and, in rare cases, pulmonary fibrosis.
Vincristine is a vinca alkaloid that interferes with microtubule formation and disrupts the tumor cytoskeleton. Typical side effects are a dose-dependent sensorimotor peripheral neuropathy, myelosuppression and constipation. Vincristine is commonly used in pediatric brain cancers because of the high sensitivity of glioma cells, whereas in adults it has a minor impact due to a poor penetration through the blood-brain barrier (BBB).
Typically, PC + CCNU + vincristine (PCV) chemotherapy is administered as an adjuvant treatment following RT in high-risk grade II and anaplastic gliomas (see Case 4.1 : Anaplastic gliomas with 1p19q co-deletion and Case 4.3 : Low-grade gliomas, later) or as a second-line chemotherapy in cases of recurrent of HGGs (see Case 4.6 : Treatment for recurrent high-grade gliomas, later) .
Nitrosourea chemotherapy
In addition to lomustine, fotemustine (diethyl 1-{1-[3-(2-chloroethyl)-3-nitro-soureido]ethyl} phosphonate (FTM) and carmustine (1,2-bis(2-chloroethyl)-1-nitrosourea; BCNU) are intravenous nitrosoureas used for treating CNS gliomas. These agents have favorable CNS characteristics, including high lipophilicity and low molecular weight, which makes, it easier to cross the BBB. The antitumor effect is based on alkylation of DNA and generation of cytotoxic damage. Similar to TMZ, the presence of methylation of MGMT confers a major sensitivity to FTM and BCNU. After intravenous infusion, the steady state is achieved within 45 minutes with a median half-life of 3 hours and a CSF concentration about 23% of plasma levels. The most important side effects are thrombocytopenia, leucopenia, and anemia. In contrast to cytopenias with temozolomide, which often remain reversible with blood counts returning to their pre-cycle baseline with each round of treatment, cytopenias with the nitrosourea compounds can be cumulative where blood counts fail to recover to their pre-cycle baseline prior to the next treatment.
Currently, CCNU, BCNU, and FTM are employed as a second-line chemotherapy in recurrent HGGs with CCNU/BCNU used in the United States and FTM used in some European countries (including Italy). They are also used as a single agent or in combination with targeted therapy (e.g., bevacizumab) in an off-label setting (see Case 4.6 : Treatment for recurrent high-grade gliomas, later).
Clinical cases
Case . A 42-year-old woman with a history of depression and chronic pain on sertraline and tramadol presented with a new contrast-enhancing lesion in the deep left frontal lobe with downward displacement of the corpus callosum and lateral ventricles. Stereotactic biopsy was performed and revealed a grade III oligodendroglioma ( IDH1 mutated, 1p/19q co-deleted, MGMT methylated). The patient was treated with radiation therapy (RT 59.4 Gy/33 fr) followed by adjuvant PCV chemotherapy. Prior to adjuvant chemotherapy, her antidepressant and tramadol were withheld due to concern about precipitating a tyramine-reaction from drug-drug interactions with procarbazine. She was instructed in a tyramine-free diet and chemotherapy was initiated. She suffered moderate treatment-induced nausea without emesis that responded to ondansetron premedication and she completed four cycles of adjuvant therapy with partial radiographic response to treatment. Despite normal blood counts prior to treatment, she experienced gradual onset of myelosuppression such that after cycle 4, her white blood cell count was 2.0 cells/mm , platelet count was 75,000 cells/mm , and further chemotherapy was withheld.
Teaching Points. This case highlights several important principles in the chemotherapeutic management of anaplastic gliomas including (1) the chemosensitivity of oligodendrogliomas, and (2) important treatment related toxicities of PCV chemotherapy. IDH mutant, 1p19q co-deleted oligodendrogliomas are among the most chemosensitive gliomas with several clinical trials having demonstrated prolonged median survival of more than 10 years with adding PCV chemotherapy to RT (see the next section). PCV chemotherapy is associated with important treatment-related toxicities and drug-drug as well as drug-diet interactions. Clinicians should be aware of the risk of a tyramine reaction in patients taking procarbazine. This catecholamine-like reaction can occur in patients who ingest or consume tyramine-containing foods or pharmacologic agents while taking PC. Patients become hypertensive often with diaphoresis, mydriasis, palpitations, headache, and chest pain. The reaction typically resolves within several hours but can be severe and require hospitalization. Patients should be counseled to avoid tyramine-containing foods including preserved meat, fish, cheese, alcohol, and other protein-rich foods.
Review of trials for co-deleted anaplastic oligodendroglioma
Interest in chemotherapy for oligodendrogliomas increased in the 1990s when responses to PCV were initially reported in small series of patients with recurrent oligodendrogliomas and oligoastrocytomas. , This was subsequently confirmed in prospective trials later. , Based on these findings, several clinical trials were designed to determine the role of PCV chemotherapy for managing anaplastic oligodendrogliomas.
RTOG 9402 Trial . The RTOG 9402 trial randomized patients with anaplastic gliomas to RT alone or neoadjuvant PCV followed by RT. It demonstrated that patients with anaplastic 1p/19q co-deleted oligodendrogliomas (i.e., co-deleted) live longer than those with absence of 1p/19q co-deletion (i.e., non–co-deleted) after the addition of PCV to RT. For patients who received PCV/RT, those with co-deleted oligodendrogliomas had a median survival of 14.7 years compared with only 2.6 years with non–co-deleted tumors (hazard ratio [HR] 0.36; 95% confidence interval [CI] 0.23–0.5; p < .001). Similarly, in patients randomized to RT alone, those with co-deleted oligodendrogliomas had a longer median survival of 7.3 years compared with only 2.7 years in non–co-deleted tumors (HR 0.40; 95% CI 0.27–0.60; p < .001). The addition of PCV significantly improved overall survival in co-deleted anaplastic oligodendrogliomas. Median OS for patients treated with PCV/RT (14.7 years) was twice that of patients receiving RT alone (7.3 years; HR 0.59; 95% CI 0.37–0.95; p = 0.03).
EORTC 26951 Trial . The European Organization for Research and Treatment of Cancer (EORTC) 26951 trial similarly randomized patients with anaplastic glioma to RT alone or RT followed by adjuvant PCV. This study showed a prolonged OS in the RT/PCV arm (42.3 months) compared with RT alone (30.6 months; HR 0.75; 95% CI 0.60–0.95). In co-deleted tumors, OS was not reached in the RT/PCV group as compared with 112 months in the RT group (HR 0.56; 95% CI 0.31–1.03).These studies established the role of PCV chemotherapy for anaplastic oligodendrogliomas with 1p19q co-deletion.
Interestingly, in the EORTC 26951 trial, only 30% of patients completed the planned six cycles of PCV due to hematologic toxicity. Considering the safety profile of PCV schedule, two surveys have shown that clinicians prefer to use TMZ rather than PCV. , Although the German NOA-4 trial on grade II gliomas did not display any difference between PCV chemotherapy and TMZ, , it is still not known whether TMZ may replace PCV. This is currently under investigation by the CODEL trial ( ClinicalTrials.gov Identifier: NCT00887146), which compares RT plus PCV versus RT plus concomitant and adjuvant TMZ for co-deleted oligodendrogliomas (both grade II and grade III).
A critical issue with regard to chemoradiation is the risk of cognitive dysfunctions in long-term survivors due to radiation neurotoxicity. Oligodendroglial tumors are considered chemosensitive. Median survival with maximum therapy is >10 years. Thus, toxicity from treatment is a major patient and provider concern. Neoadjuvant chemotherapy with alkylating agents could be used as the initial up-front treatment in 1p/19q co-deleted oligodendrogliomas in order to delay salvage RT to progression. This is currently being investigated in the POLCA trial, which compares initial treatment with RT and PCV versus PCV alone (RT being postponed at the time of progression) in 1p/19q co-deleted anaplastic oligodendrogliomas ( ClinicalTrials.gov Identifier: NCT02444000).
Clinical Pearls and Treatment Recommendations in Daily Practice
Taken together, the long-term results of the RTOG 9402 and the EORTC 26951 trials suggest that 1p/19q co-deletion identifies slow-growing tumors that respond to chemotherapy and may be controlled for many years with RT plus PCV. Hence, combined treatment with RT and PCV should be the SOC in co-deleted anaplastic oligodendrogliomas as defined by the recent WHO 2016 classification (see Chapter 1 for more discussion of histopathologic classification). Some have also suggested that diffuse gliomas with astrocytic phenotype (that by definition are IDH 1-2 mutated) should be treated similar to 1p/19q co-deleted anaplastic oligodendrogliomas.
Case . A 35-year-old woman presented with a tonic-clonic seizure on the left side. Brain MRI showed a bilateral frontal T2/fluid attenuated inversion recovery (FLAIR) lesion without contrast enhancement. The patient underwent a subtotal resection ( Fig. 4.1A ) and was started an antiepileptic therapy with levetiracetam 2000 mg/day. The histological examination revealed a grade III astrocytoma ( IDH1 mutated, 1p/19q non–co-deleted, MGMT unmethylated). The patient was enrolled in the CATNON trial and was randomized for the arm 3 (RT 59.4 Gy/33 fr plus adjuvant TMZ 150–200 mg/m 2 for 5 consecutive days/28 days for 12 cycles). The brain MRI after the completion of 12 cycles of chemotherapy displayed a partial response on T2/FLAIR sequences without contrast enhancement on T1-weighted sequence and lower relative cerebral blood volume (rCBV) value on perfusion MRI ( Fig. 4.1B ).
Teaching Points. This case highlights the fact that, unlike co-deleted anaplastic oligodendrogliomas which tend to be extremely chemosensitive, similar results have not been observed for non–co-deleted anaplastic astrocytomas. The majority of these tumors will be IDH mutated with variable MGMT promoter methylation. As in this case, following maximal safe resection, radiation therapy remains the backbone of adjuvant treatment. The role of chemotherapy has been and continues to be investigated in clinical trials with initial results suggesting a benefit, particularly in IDH mutant gliomas.
Review of trials for non–co-deleted anaplastic astrocytoma
RTOG 9402 and EORTC 26951 . The use of PCV chemotherapy for non–co-deleted anaplastic gliomas was assessed in both the RTOG 9402 and EORTC 26951 trials. Both studies did not show a statistically significant OS benefit of adjuvant RT plus PCV as compared with RT alone in patients without 1p/19q co-deletion. Median OS was similar for both treatment groups in the RTOG 9402 trial (2.6 years vs 2.7 years, respectively; HR 0.85; 95% CI 0.58–1.23; p = 0.39) and in the EORTC 26951 trial (25 months vs 21 months; HR 0.83; 95% CI 0.62–1.10). These data highlight the conventional opinion that non–co-deleted tumors are characterized by a lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted gliomas.
CATNON . Following these studies, the role of chemotherapy in newly diagnosed non–co-deleted anaplastic gliomas was further investigated by the phase III EORTC 26053-22054 CATNON trial (Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma, ClinicalTrials.gov Identifier: NCT00626990). This trial was designed to address the role of adjuvant TMZ for the treatment of non–co-deleted anaplastic gliomas. In this study, patients were randomized 1:1:1:1 into four different treatment arms: (1) RT alone (59.4 Gy in 33 fractions); (2) RT plus adjuvant TMZ (12 4-week cycles of 150–200 mg/m 2 per day); (3) RT plus concomitant TMZ (75 mg/m 2 per day during radiotherapy); (4) RT plus concomitant and adjuvant TMZ (Stupp regimen). The first interim analysis of the CATNON trial showed a significant advantage in progression-free survival (PFS) for patients receiving adjuvant TMZ (42.8 months; 95% CI 28.6–60.6; 5-year PFS 43.1%) over those not receiving adjuvant TMZ (19.0 months; 95% CI 14.4–24.6; 5-year PFS 24.3%). The same was true for OS (not reached; 5-year OS 55.9% vs 41.1 months; 95% CI 36.6–60.7; 5-year OS 44.1%). The multivariable analysis showed that age >50 years (HR 4.04; 95% CI 2.78–5.87; p = 0.0001) was a risk factor for poorer survival, whereas administration of adjuvant TMZ (HR 0.65; 95% CI 0.45–0.93; p 0.0014) and MGMT promoter methylation (HR 0.49; 95% CI 0.26–0.93; p = 0.0031) were associated with longer survival.
Clinical Pearls and Treatment Recommendations in Daily Practice
The SOC for 1p/19q non–co-deleted anaplastic gliomas includes maximal safe resection, RT, and TMZ-based chemotherapy. Some questions still remain, including the specific timing and sequence of TMZ and the role of molecular profiling, to inform personalization of treatment.
In current practice, these patients may receive RT followed by 12 cycles of adjuvant TMZ or RT with concurrent TMZ followed by 6 cycles of adjuvant TMZ. A meta-analysis on GBM has suggested that the efficacy of 6 rather than 12 cycles of adjuvant TMZ are equivalent. However, it is unknown whether six cycles of TMZ may lead to the same outcome in PFS and OS for anaplastic grade III gliomas. Moreover, prior trials were started before the identification of the isocitrate dehydrogenase ( IDH ) 1/2 mutations as a marker of glioma of prognostic significance. Further retrospective molecular analysis, including IDH1/2 and MGMT methylation status, may help to identify those patients who will benefit most from TMZ. Lastly, further follow-up is needed to evaluate the impact of concomitant TMZ in improving OS. In particular, the second-interim analysis of the CATNON trial revealed that concurrent chemoradiation does not provide a significant increase in OS. However, a trend toward a benefit of concomitant chemoradiation is observed in IDH mutated tumors, but not in IDH wild-type tumors.
Case . In June 2005, a 50-year-old man had partial seizures with secondary generalization. Brain MRI showed a mild patchy enhancing lesion on the right temporo-insular lobe without significant mass effect ( Fig. 4.2A ). The patient was started on antiepileptic therapy (oxcarbazepine 900 mg/day and levetiracetam 2000 mg/day) and underwent a subtotal resection. The histological examination revealed a grade II oligodendroglioma ( IDH1 mutated, 1p/19q co-deleted, MGMT methylated). Considering the favorable molecular profile and the presence of residual tumor, the patient received up-front chemotherapy with 1 week-on/1 week-off TMZ (150 mg/m 2 per day). The patient achieved a significant reduction of seizure frequency, as well as a complete response on contrast enhanced T1-weighted sequence and minor response on T2/FLAIR sequence in brain MRI (RANO criteria) ( Fig. 4.2B ) after 12 cycles of chemotherapy. The clinical and radiological response lasted until December 2015.
Teaching Points. Low-grade gliomas are a heterogeneous group of tumors that include pure oligodendrogliomas, IDH mutant astrocytomas, and IDH wild-type astrocytomas. Mixed oligoastrocytomas have essentially been removed by integrating molecular assessment into glioma classification (see Chapter 1 , Cases 1.2 and 1.3 for further discussion of molecular classification of low-grade gliomas). This case highlights the role of chemotherapy for low-grade gliomas. Historically, LGGs were thought to not be chemosensitive to alkylating therapy due to their slow-growing biology. However, recent clinical trials have demonstrated favorable outcomes in patients with 1p19q co-deleted oligodendrogliomas and frequently for IDH mutant astrocytomas, compared with IDH wild-type low-grade gliomas which have largely not been responsive to chemotherapy.
Review of trials for low-grade glioma
Three pivotal phase III trials inform the chemotherapy management of LGGs including EORTC 22845, RTOG 9802, and EORTC 22033-26033. Historically, RT was the initial treatment for all low-grade gliomas.
EORTC 22845 Trial . This phase III trial addressed the question of timing of radiation for LGGs. Patients with LGG were randomized to early versus delayed RT. Early RT improved median PFS compared with delayed RT at tumor progression (early RT: 5.3 years; delayed RT: 3.4 years; HR 0.59; 95% CI 0.45–0.77; p < .0001) and improved seizure control at 1 year. However, median OS was not different (early: 7.4 years; delayed RT: 7.2 years; HR 0.97; 95% CI 0.71–1.34; p = 0.872.
RTOG 9802 Trial . In 1998, the phase III RTOG 9802 trial was launched by the Radiation Therapy Oncology Group comparing RT with or without adjuvant PCV. The publication of a preliminary analysis of this trial in 2012 did not report an OS advantage with the addition of chemotherapy despite an improvement of PFS. Notably, OS and PFS curves matched for all patients between years 0 and 2, but separated significantly after 2 years, favoring RT + PCV. A similar trend was noted for OS. With a longer follow-up, a statistically significant benefit in OS for the RT plus PCV arm was observed (13.3 years, 95% CI 10.6–not reached; 5-year OS 72%, 95% CI 64–80) as compared with RT alone (7.8 years, 95% CI 6.1–9.8; 5-year OS 63%, 95% CI 55–72; HR 0.59, p = 0.003). In parallel, patients who received RT plus PCV displayed a longer PFS (median PFS 10.4 years, 95% CI 6.1–not reached) than those treated with RT alone (median PFS 4.0 years, 95% CI 3.1–5.5; HR 0.50; p < 0.001). Patients with IDH1 mutation had a longer OS (13.1 years, 95% CI 10.1–not reached) than those without IDH1 mutation (5.1 years, 95% CI 1.9–11.5). The longest survival was observed in IDH1 mutant gliomas who received RT and PCV. Multivariable analysis revealed that age <40 years, oligodendroglial tumor, and chemoradiation are favorable prognostic factors for both PFS and OS. IDH1 mutation was correlated with a better PFS, but not statistically significant for OS.
EORTC 22033-26033 . The risk of a neurocognitive impairment in long-term survivors after 8–12 years following RT led a number of clinicians to postpone the use of RT in favor of up-front chemotherapy. In this regard, the aim of the phase III EORTC 22033-26033 study investigated whether the dose-dense TMZ was superior to standard radiation therapy in high-risk LGGs. No difference in median PFS was observed between the two arms (TMZ arm: 39 months; 95% CI 35–44; RT arm: 46 months; 95% CI 40–56; HR 1.16; 95% CI 0.9–1.5, p = 0.22). For patients with IDH1/2 mutation and 1p/19q co-deletion, outcomes were similar (TMZ arm: 55.0 months; RT arm: 61.6 months). However, for patients with IDH1/2 mutation and absence of 1p/19q co-deletion, median PFS was longer for those receiving RT (55 months, 95% CI 48–66) compared with TMZ (36 months, 95% CI 28.4–47; HR 0.53; 95% CI 0.35–0.82; p = 0.0043). These results suggest that RT may be superior to chemotherapy in astrocytomas. However, data on OS are needed to confirm this preliminary analysis.
A retrospective analysis conducted by the US National Cancer Database showed that chemotherapy alone may be more effective compared with RT alone in oligodendroglial tumors, but not in astrocytomas. Furthermore, a retrospective study of the US National Cancer Database has reported that chemotherapy alone confers a similar OS compared with chemoradiation, but the median follow-up was short (4.6 years) with inability to reveal the late effect of chemoradiation.
TMZ alone after surgery may represent an option, especially in oligodendroglial tumors that are more chemosensitive, in order to delay RT and the risk of cognitive impairment. Wahl and colleagues reported a median PFS and OS of 4.2 and 9.7 years, respectively, in a cohort of high-risk LGGs treated with TMZ alone following initial surgery. Similarly, the phase II AINO study showed a PFS of 4.2 years and an OS of 9.8 years in oligodendrogliomas IDH -mutant and 1p/19q co-deleted, which are comparable to the EORTC (4.6 years) and Wahl (4.9 years) studies. Interestingly, both studies demonstrated a median time to delay of RT of 5.8 and 8.2 years, respectively.
Clinical Pearls and Treatment Recommendations in Daily Practice
Like anaplastic gliomas, certain histomolecular LGG subtypes are chemotherapy responsive. The recent phase II and III trials provide helpful guidance. First, RT alone may be comparable to TMZ alone as initial therapy for certain LGGs, particularly those with IDH mutation, given that PFS of patients receiving TMZ alone in the EORTC 22033-26033 is similar to that of patients treated with RT alone in EORTC 22845 and RTOG 9802 trials. Second, PCV with RT should be considered SOC for LGGs, particularly oligodendrogliomas. However, the impact of combined treatment on neurocognitive functions and quality of life is still unknown. Whether a sequential approach, consisting of TMZ as initial treatment with reoperation and/or RT plus PCV at tumor relapse, has the same impact of early RT plus PCV in balancing survival and cognitive preservation for patients with high-risk co-deleted oligodendrogliomas is unsolved, and can justify the use of chemotherapy alone as initial therapy. Lastly, both TMZ and PCV may favorably impact seizures and are considered as a biomarker of treatment efficacy. , ,
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