Upfront Treatment with Cisplatin

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  Cisplatin has a long history of therapeutic use in high-grade gliomas. In clinical use, cisplatin is often given in combination with other chemotherapies. In 1992 Yung and colleagues conducted a single-arm study to test the efficacy of using alternating courses of 1,3-bis(2-chloroethyl)-1 nitrosourea (BCNU, carmustine) and CDDP in conjunction with radiation therapy after surgical resection to treat primary malignant glioma. Patients with histologic diagnosis of GBM, anaplastic astrocytoma, and anaplastic oligodendroglioma underwent surgical resection or biopsy. Radiotherapy was initiated over 6 to 7 weeks, and chemotherapy was started during the first week of radiotherapy. A total of 33 patients entered the analysis, with a median time to tumor progression of 32 weeks for patients with glioblastoma and 50 weeks for those with anaplastic glioma. Median survival time was 55 weeks for glioblastoma and 110 weeks for anaplastic glioma. The 18-month survival rate was 55% overall. The results of this study suggested that BCNU alternating with CDDP in conjunction with radiotherapy is safe and also indicated that there may be benefits in OS over radiotherapy with BCNU alone.

  
  
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  Lassen and colleagues investigated the use of CDDP as part of a combination therapy for newly diagnosed GBM. This study was a single-arm phase II trial examining the efficacy of a combination of cisplatin, BCNU, and etoposide, followed by radiation. All patients underwent tumor resection, and then chemotherapy was started 2 to 4 weeks after surgery. The primary end point of the study was response to chemotherapy using the MacDonald criteria. Radiographic partial response was achieved by 32% of patients, 39% had stable disease, and 29% had progressive disease. Complete response was not achieved in any patient. Median time to progression was 7.6 months and median survival was 11.4 months. The investigators concluded that although the survival benefit fell short of historical data, a potential benefit from the regimen used in the study was the shorter total treatment time of preradiation chemotherapy making it potentially less cumbersome.

  
  
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  In 2009 Silvani and colleagues conducted a retrospective study examining the clinical effectiveness of using the combination of CDDP and BCNU as the first-line management of GBM. One hundred sixty patients received chemotherapy and radiotherapy in a tandem fashion. After chemotherapy, radiotherapy was administered at 1.8 to 2.0 Gy/d to a total of 60 Gy. The next cycle of chemotherapy was started after radiotherapy was completed and subsequent cycles started every 6 weeks for a total of 5 cycles. Patients in this study had a median PFS of 7.6 months and median OS of 15.6 months. Although the survival results of the study are comparable with those of Stupp and colleagues with TMZ, regarding the clinical benefit of cisplatin and BCNU, the toxicities were comparably worse. The results of this large trial of CDDP in GBM are compared in Table 1 .

  
  
  
  

  Table 1

  
  

  Comparison of cisplatin-based chemotherapies in high-grade gliomas

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Trial	Tumor Type	Timing of Treatment	Number of Patients	Chemotherapy	Median PFS (wk)	Median OS (wk)
  Yung et al, 1992	Grade III/IV	Upfront	33	BCNU + CDDP	50/32	110/55
  Shinoda et al, 1997	GBM	Upfront	30	CDDP	16	60
  Lassen et al, 1999	GBM	Upfront	27	BCNU + CDDP + Etoposide	30.4	45.6
  Silvani et al, 2009	GBM	Upfront	160	BCNU + CDDP	30.4	62.4

  
  

Cisplatin Toxicity

The main difficulty in the use of cisplatin is its toxicity profile. Hematologic side effects are the most common and tend to be the most severe. Hematologic toxicity was significant with grade 4 leukopenia and thrombocytopenia occurring in 10% and 57% respectively. Ototoxicity is also frequent, making this a drug that must be used with caution. Clinically significant hearing loss and tinnitus can be seen in 13% to 19% of patients at 6 months after treatment with cisplatin, with 36% having evidence of sensorineural hearing loss on audiogram testing.

Upfront Treatment with Cisplatin

• •
  

  Cisplatin has a long history of therapeutic use in high-grade gliomas. In clinical use, cisplatin is often given in combination with other chemotherapies. In 1992 Yung and colleagues conducted a single-arm study to test the efficacy of using alternating courses of 1,3-bis(2-chloroethyl)-1 nitrosourea (BCNU, carmustine) and CDDP in conjunction with radiation therapy after surgical resection to treat primary malignant glioma. Patients with histologic diagnosis of GBM, anaplastic astrocytoma, and anaplastic oligodendroglioma underwent surgical resection or biopsy. Radiotherapy was initiated over 6 to 7 weeks, and chemotherapy was started during the first week of radiotherapy. A total of 33 patients entered the analysis, with a median time to tumor progression of 32 weeks for patients with glioblastoma and 50 weeks for those with anaplastic glioma. Median survival time was 55 weeks for glioblastoma and 110 weeks for anaplastic glioma. The 18-month survival rate was 55% overall. The results of this study suggested that BCNU alternating with CDDP in conjunction with radiotherapy is safe and also indicated that there may be benefits in OS over radiotherapy with BCNU alone.

  
  
• •
  

  Lassen and colleagues investigated the use of CDDP as part of a combination therapy for newly diagnosed GBM. This study was a single-arm phase II trial examining the efficacy of a combination of cisplatin, BCNU, and etoposide, followed by radiation. All patients underwent tumor resection, and then chemotherapy was started 2 to 4 weeks after surgery. The primary end point of the study was response to chemotherapy using the MacDonald criteria. Radiographic partial response was achieved by 32% of patients, 39% had stable disease, and 29% had progressive disease. Complete response was not achieved in any patient. Median time to progression was 7.6 months and median survival was 11.4 months. The investigators concluded that although the survival benefit fell short of historical data, a potential benefit from the regimen used in the study was the shorter total treatment time of preradiation chemotherapy making it potentially less cumbersome.

  
  
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  In 2009 Silvani and colleagues conducted a retrospective study examining the clinical effectiveness of using the combination of CDDP and BCNU as the first-line management of GBM. One hundred sixty patients received chemotherapy and radiotherapy in a tandem fashion. After chemotherapy, radiotherapy was administered at 1.8 to 2.0 Gy/d to a total of 60 Gy. The next cycle of chemotherapy was started after radiotherapy was completed and subsequent cycles started every 6 weeks for a total of 5 cycles. Patients in this study had a median PFS of 7.6 months and median OS of 15.6 months. Although the survival results of the study are comparable with those of Stupp and colleagues with TMZ, regarding the clinical benefit of cisplatin and BCNU, the toxicities were comparably worse. The results of this large trial of CDDP in GBM are compared in Table 1 .

  
  
  
  

  Table 1

  
  

  Comparison of cisplatin-based chemotherapies in high-grade gliomas

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Trial	Tumor Type	Timing of Treatment	Number of Patients	Chemotherapy	Median PFS (wk)	Median OS (wk)
  Yung et al, 1992	Grade III/IV	Upfront	33	BCNU + CDDP	50/32	110/55
  Shinoda et al, 1997	GBM	Upfront	30	CDDP	16	60
  Lassen et al, 1999	GBM	Upfront	27	BCNU + CDDP + Etoposide	30.4	45.6
  Silvani et al, 2009	GBM	Upfront	160	BCNU + CDDP	30.4	62.4

  
  

Cisplatin Toxicity

The main difficulty in the use of cisplatin is its toxicity profile. Hematologic side effects are the most common and tend to be the most severe. Hematologic toxicity was significant with grade 4 leukopenia and thrombocytopenia occurring in 10% and 57% respectively. Ototoxicity is also frequent, making this a drug that must be used with caution. Clinically significant hearing loss and tinnitus can be seen in 13% to 19% of patients at 6 months after treatment with cisplatin, with 36% having evidence of sensorineural hearing loss on audiogram testing.

Irinotecan in Recurrent Disease

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  The use of irinotecan as a single agent has had mixed results and is complicated by interactions with CYP inducers. A prospective phase II study by Chamberlain of CPT-11 in 40 patients with recurrent supratentorial GBM failed to show a tumor response to treatment although the dosages used, 400 to 500 mg/m ² every 3 weeks, were suboptimal. Anticonvulsant medications with cytochrome P450–inducing features upregulate chemotherapy catabolism. It was suggested that the dosages used may have been insufficient because more than 60% of patients were on anticonvulsant therapy.

  
  
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  Only 48% of patients enrolled in the Friedman and colleagues’ phase II study of recurrent or progressive malignant gliomas received enzyme-inducing antiepileptic drugs. In this population of 80% GBM, the 60 patients enrolled experienced a median time to tumor progression of 12 weeks and a median estimated survival of 43 weeks. Confirmed partial responses on magnetic resonance imaging were seen in 15% of patients, whereas stable disease was achieved in 55% of radiographic responses.

Enzyme-Inducing Antiepileptic Drugs Affect the Dosing of Irinotecan

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  The effects of receiving enzyme-inducing antiepileptic drug (EIAED) therapy were taken into account in the phase II North American Brain Tumor Coalition (NABTC) study in recurrent malignant gliomas treated with irinotecan. Irinotecan was administered at 350 mg/m ² every 3 weeks in those not on EIAED therapy and 750 mg/m ² in those on EIAED therapy until progression or a total of 12 months of treatment. Patients with GBM accounted for 75% of 51 total patients enrolled. Overall, 17.6% of the patients were PFS-6. A partial radiographic response was seen in 5.8%, stable disease in 33%, and immediate progression was seen in 58.8% of the group. The predetermined PFS-6 efficacy of at least 30% was not met, leading the study investigators to conclude that efficacy was not established in this population.

  
  
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  In the New Approaches to Brain Tumor Therapy (NABTT) 97-11 study, they attempted to mitigate the varied doses of prior trials and the influence of EIAED therapy by treating at the maximum tolerated dose (MTD) of irinotecan for those patients on EIAED therapy (group A) and those who were not (group B). Group A was treated with an infusion of 411 mg/m ² every week for 4 consecutive weeks out of a 6-week cycle, whereas group B received 117 mg/m ² . The primary end point was the radiographic response: 6% experienced a complete response, there were no partial responses, 28% had stable disease, and another 28% experienced disease progression during treatment. Median PFS was 7.3 months, PFS-6 was 56%, and median OS was 10.4 months. Phase I of this trial was closed after 18 patients because of the failure to meet the minimum requirement of more than 2 responses.

Irinotecan Toxicity

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  Common toxicities seen in single-agent CPT-11 were diarrhea, nausea and vomiting, and neutropenia. In CNS disease, toxicities were less frequently seen than in colorectal studies of similar doses because of the increased metabolism of CPT-11 caused by the CYP450-inducing antiepileptic drugs with subsequent increases in irinotecan clearance. The frequency of grade 3/4 diarrhea was 33.7% and grade 3/4 neutropenia was 28% in colorectal studies. In those patients treated at the MTD, grade 3/4 toxicities were encountered in 67% of patients. Anticholinergic symptoms are frequently seen and commonly pretreated with atropine during infusion. The equivocal efficacy data on single-agent CPT-11 led to postulation about its role in combination therapy with newer treatments.

Irinotecan in the TMZ Era

With the statistically significant survival benefits of the alkylating agent, TMZ, along with minimal toxicity, the Stupp regimen has become the standard care for newly diagnosed GBM. The role of irinotecan in addition to TMZ has been investigated in the NABTT study along with the pharmacokinetics of the combination in patients receiving EIAED therapy.

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  In this dose-escalation study of irinotecan combined with TMZ, the starting dose of irinotecan was 350 mg/m ² , which was escalated in 50 mg/m ² increments to 550 mg/m ² . The MTD in the study was 500 mg/m ² . Twenty-six out of 33 patients had GBMs, one was diagnosed with gliosarcoma and the remainder of the patients had anaplastic gliomas. Radiographic complete response was seen in 6%, partial response in 19%, stable disease in 36%, and progressive disease in 39%.

  
  
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  Quinn and colleagues studied the use of TMZ plus irinotecan in 42 newly diagnosed patients with GBM before treatment with radiotherapy at the end of cycle number 3 in a phase II trial. Irinotecan was infused on days 1, 8, 22, and 29 of each cycle, with those on EIAED therapy receiving 325 mg/m ² and 125 mg/m ² for those not receiving EIAED therapy. The radiographic response consisted of 19% partial responses and 50% with stable disease. Median PFS was 3.1 months and median OS was 13.8 months. Disappointingly, the study failed to meet the predetermined response rate of greater than or equal to 26% required to proceed with a phase III trial and had grade 3/4 adverse events of up to 36%. Of interest, the level of O ⁶ -methylguanine-DNA methyltransferase (MGMT) expression in this study failed to show a statistically significant relationship between PFS and OS as would be expected from treatment with TMZ.

Irinotecan in the Bevacizumab Era

The introduction of the humanized immunoglobulin G ₁ monoclonal antibody that selectively inhibits vascular endothelial growth factor, bevacizumab, has changed the way chemotherapies, such as irinotecan, are used. FDA approval for bevacizumab in the recurrent setting was established in 2009 based on response data from the following study.

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  The prospective phase II trial by Vrendenburgh and colleagues evaluated bevacizumab plus irinotecan in 35 patients with recurrent GBM initially treated with radiotherapy and concurrent TMZ. Two dosing schedules were used, most patients received bevacizumab at 10 mg/kg and irinotecan every 2 weeks, with those on EIAEDs receiving 340 mg/m ² and those not on EIAEDs receiving 125 mg/m ² . There was no difference between the 2 groups statistically. A radiographic partial response was seen in 57% of patients by the Macdonald criteria. The median PFS was 24 weeks and median PFS-6 was 46%, far exceeding the predetermined 20% decision rule for effectiveness. The 6-month OS was 77% and the median OS was 42 weeks.

  
  
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  The benefit of bevacizumab alone or in combination with CPT-11 was evaluated by Friedman and colleagues in a phase II, multicenter, noncomparative trial in recurrent glioblastoma. The PFS-6 rates were 42.6% and 50.3%, and the median OS times were 9.2 months and 8.7 months, respectively, for bevacizumab alone and bevacizumab/CPT-11 groups.