- Email: [email protected]
Long-term use of temozolomide: Could you use temozolomide safely for life in gliomas?
854
Case Reports / Journal of Clinical Neuroscience 16 (2009) 854–855
Long-term use of temozolomide: Could you use temozolomide safely for life in gliomas? Mustafa Khasraw *, David Bell, Helen Wheeler Department of Medical Oncology, Royal North Shore Hospital, Pacific Highway, St Leonards, New South Wales 2065, Australia
a r t i c l e
i n f o
Article history: Received 11 July 2008 Accepted 14 September 2008
Keywords: Temozolomide Glioma Glioblastoma multiforme
a b s t r a c t Temozolomide (TMZ) is an alkylating agent used in the management of gliomas. Although TMZ is generally safe and acute toxicity is well documented, there are limited data on long-term toxicities. We present three patients with glioma; all patients started on TMZ after having progressed following primary treatment. These patients have continued TMZ for 5 years, 7 years and 8 years respectively. So far they have had no serious side effects. We discuss these patients while raising the question of prolonged TMZ use. Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
1. Introduction The combination of surgery, radiation and temozolomide (TMZ) has become the standard therapy for patients with newly diagnosed malignant gliomas; however, no standard has emerged for recurrent disease. TMZ has been used for this group of patients either alone or in combination with other agents. The optimal dosing and duration of TMZ is still a matter of debate. We report three patients undergoing prolonged therapy with TMZ. With the limitation of this being only a retrospective report, it confirms that prolonged therapy is possible for those patients who remain sensitive to the drug. Two patients progressed on cessation of therapy and reinstitution of the drug led to long-term tumour control. 2. Case 1 A 49-year-old man presented with seizures, right-sided weakness and dysphasia. An MRI revealed an enhancing mass in keeping with a left frontal high-grade glioma. A craniotomy and brain biopsy diagnosed a gemistocytic astrocytoma. He was treated with 6 weeks of primary radiotherapy. The patient developed worsening weakness, dysphasia and headaches while we were trying to reduce dexamethasone to a dose lower than 8 mg/day. A brain MRI shortly after the radiotherapy showed a large cystic and partly solid left frontal lobe mass with significant edema and midline shift. Four months later a repeat craniotomy was undertaken with further optimal debulking. Histopathology revealed persistent gemistocytic astrocytoma with foci of incipient necrosis consistent with World health Organization (WHO) grade 3 anaplastic astrocytoma. A subsequent follow-up MRI 5 months later showed recurrent tumour, with solid and cystic components but no edema or mass effect. The patient was commenced on TMZ 200 mg/m2 for 5 days every 4 weeks. On follow-up, a progress MRI 6 months after commencing TMZ was unchanged and the patient remained clinically well. He continued TMZ. An MRI 12 months after commencing TMZ showed reduction in size of the tumour. Although we recommended that he cease TMZ treatment, the patient was reluctant to cease this agent in view of his stable condition. He continues on the day 1 to day 5 TMZ 200/m2 every 4 weeks and has not developed any bone marrow toxicity. He remains well after 5 years (62 months) * Corresponding author. Tel.: +61 2 9926 5020; fax: +61 2 9906 4150. E-mail address: [email protected] (M. Khasraw).
of TMZ treatment and his MRI has remained stable. Although he is not employed, he has normal functional capacity and an Eastern Cooperative Oncology Group (ECOG) performance status of 0. 3. Case 2 An 18-year-old man presented with a 4-week history of ataxia and dysarthria, bilateral nystagmus and partial right-sided trigeminal and facial nerve palsies. MRI showed a cystic 4 cm by 5 cm right cerebral peduncle tumor with associated edema and compression of the fourth ventricle. The histopathology from surgical debulking revealed pilocytic astrocytoma (WHO grade 1). The patient recovered postoperatively and remained stable until his gait deteriorated gradually 15 months later when an enlarging cystic recurrence was seen on follow-up MRI. Two months later he underwent a right posterior fossa craniotomy and drainage of a cerebellopontine angle cyst with the insertion of an ommaya reservoir into the cystic cavity. He recovered well and regained normal function and even returned to work as a building inspector. However, 1 year later, he had a local recurrence noted at the resection bed on MRI. He had another right posterior fossa craniotomy with re-excision of the recurrent tumor and removal of the reservoir. Histopathology reconfirmed the presence of pilocytic astrocytoma. The patient remained well and was walking unaided for another 6 months when he developed ataxia. Another cystic recurrence was noted on imaging for which he underwent a further craniotomy. Six months later the patient started to have more headaches; his general condition deteriorated and he developed a significant right-sided weakness. An MRI revealed a multicystic component and a solid area of recurrence. After four craniotomies, with decreasing time to recurrence, we thought that further adjuvant options needed to be considered. Due to his poor performance status he was not a candidate for radiotherapy. He was commenced on TMZ 200 mg/m2 for 5 days every 4 weeks. After four cycles the patient was improving clinically and TMZ was continued. The patient insisted on continuing therapy. After 3 years an MRI showed only minor enhancement at the surgical bed and the patient was convinced to cease TMZ. Unfortunately a repeat MRI 3 months after the cessation showed increased areas of enhancement in the cerebellum and brainstem. TMZ was again recommenced and since then the patient has remained both clinically and radiologically stable; however, he does have some right-sided weakness but he is able to use a walking frame outside his house. There are only minimal residual changes
Case Reports / Journal of Clinical Neuroscience 16 (2009) 854–855
on his last MRI. In 2008, after about 8 years (94 months) of TMZ chemotherapy, he remains well with a normal cognitive function but a degree of mobility limitation with an ECOG performance status of 1. 4. Case 3 A 31-year-old man presented with seizures in 1997. A CT scan showed a left frontoparietal tumor. A debulking craniotomy was undertaken. Histopathology confirmed a glioblastoma multiforme (GBM) (WHO grade 4). Adjuvant radiotherapy was administered with 60 Gy in 30 fractions followed by a stereotactic boost. He remained well for 2 years, after which he started to have seizures. He has developed a right-sided weakness. He was commenced on 12 mg of dexamethasone, carabamazepine and gabapentin. An MRI performed 4 days later revealed enhancement at the resection area consistent with recurrence of the GBM with significant edema. A fluorodeoxyglucose-positron emission tomography (FDG-PET) scan revealed increased uptake at the tumour area. Shortly afterwards he had a second craniotomy and tumor debulking. Postoperatively he remained on 8 mg of dexamethasone. Histopathology from the second craniotomy showed radiation necrosis only. He was enrolled in a clinical trial using thalidomide after the second craniotomy. However, 1 month later the patient had more seizures and his right hemiparesis deteriorated. Dexamethasone was increased to 16 mg/day. An MRI showed increase in the area of enhancement. The thalidomide dose was increased from 400 mg/day to 500 mg/day. Lack of response after 7 months of thalidomide prompted exploring other therapeutic options. TMZ 200 mg/m2 was commenced daily for 5 days every 4 weeks (as soon as it became available in Australia). The patient improved clinically, and dexamethasone was tapered. MRI appearances remained stable for 18 months and a repeat FDG-PET showed no uptake. TMZ was ceased. Unfortunately 4 months after cessation his MRI showed further progression, repeat PET showed new uptake and TMZ was recommenced. Two years later when MRI had improved and a new FDG-PET showed no uptake, another attempt to wean the TMZ was made by increasing the cycle intervals to 5 weeks. Unfortunately his MRI 7 months later showed progression of the tumor, which necessitated changing the treatment regime back to every 4 weeks. Eight years (98 months) since commencing TMZ the patient is stable with a degree of expressive dysphasia and an ECOG performance status of 1. 5. Discussion Prior to the introduction of TMZ, nitrosoureas were used for recurrent glioma. Nitrosureas cause significant marrow toxicity and other problematic side effects such as pulmonary fibrosis. TMZ is less toxic than nitrosoureas and since its introduction the treatment of gliomas and especially GBM has changed significantly. This is mainly since Stupp et al. in 2005 showed a significant 2-year survival rate of 26.5% with radiotherapy plus TMZ compared to 10.4% with radiotherapy alone.1 This trial has shown that the addition of TMZ to radiotherapy for newly diagnosed glioblastoma resulted in a statistically significant and clinically meaningful survival benefit with minimal additional toxicity. This has become the standard of care for adjuvant therapy for newly diagnosed patients with GBM. Concomitant treatment with radiotherapy plus TMZ resulted in grade 3 or 4 hematologic toxic effects in 7% of patients.1 Prolonged and severe pancytopenia after low dose continuous TMZ concurdoi:10.1016/j.jocn.2008.09.005
855
rently with cranial radiotherapy has been reported.2 There have also been reports of three patients who developed severe neutrophil dysfunction after one cycle of TMZ. It is well known that many alkylating agents can lead to secondary cancers such as acute myeloid leukemia, years after the therapy. Two cases of TMZ-related myelodysplasia and acute myeloid leukemia after 6 months to 2 years of TMZ treatment have been reported.3,4 Both these cases had previous treatment with other alkylating agents, which might have contributed. Our three patients with gliomas had progressed following surgical and radiation treatment (in the second case the patient was declined radiotherapy because of his poor performance status). These three patients have continued TMZ for 5 years, 7 years and 8 years respectively. They have, so far, had no significant hematological toxicity and no opportunistic infections. Two of the reported cases had documented disease progression upon ceasing TMZ and responded remarkably when TMZ was reintroduced. The ideal treatment length with TMZ is uncertain in this population.5,6 There has been a reported advantage to having more than 19 months of therapy, although this report has limitations, and has not been published in a peer-reviewed paper.6 However, it is generally accepted that long-term therapy with nitrosureas is not possible, given the progressive myelosuppression that ensues even in patients who respond to therapy. Many patients progress during or after first-line therapy and second-line regimens are only modestly active. Continuous dosing and dose intensification may decrease levels of O-6-methylguanine-DNA methyltransferase, which has been associated with TMZ resistance. Altering the schedule of TMZ and dose intensification may reinduce chemosensitivity.7 Significant toxicity is uncommon with TMZ, but may be significant for those at risk. Use of a clinical model to predict risk may allow for individualized dosing and management.8 TMZ is also being combined increasingly with biologic or targeted therapies and antiangiogenic agents. With the limitation of this being only a retrospective report, we suggest that unlike most patients who become resistant to TMZ at relapse, there might be a subset of patients who remain sensitive and continue to respond to this drug. Concerns about toxicity and also important health economic implications for prolonged use of TMZ will need be addressed as survival of these patients is increasing, albeit with small increments. References 1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–96. 2. Singhal N, Selva-Nayagam S, Brown MP. Prolonged and severe myelosuppression in two patients after low-dose temozolomide treatment- case study and review of literature. Neuro Oncol 2007;85:229–30. 3. Noronha V, Berliner N, Ballen KK, et al. Treatment-related myelodysplasia/AML in a patient with a history of breast cancer and an oligodendroglioma treated with temozolomide: case study and review of the literature. Neuro Oncol 2006;8:280–3.. Epub 2006 May 25. 4. Su YW, Chang MC, Chiang MF, et al. Treatment-related myelodysplastic syndrome after temozolomide for recurrent high-grade glioma. J Neurooncol 2005;71:315–8. 5. Hau P, Koch D, Hundsberger T, et al. Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. Neurology 2007;68:688–90. 6. Colman H, Hess K, Turner M, et al. Impact of duration of temozolomide therapy on progression-free survival in recurrent malignant glioma. Neuro Oncol 2002;4:368. (Abstract). 7. Perry J, Mason W, Belanger K. The temozolomide RESCUE study: A phase II trial of continuous (28/28) dose-intense temozolomide (TMZ) after progression on conventional 5/28 day TMZ in patients with recurrent malignant glioma. J Clin Oncol 26:2008 (May 20 suppl; abstr 2010) Abstract. 8. Armstrong T, Cao Y, Vera E, et al. Pharmacoepidemiology of myelotoxicity (TOX) with temozolomide (TMZ) in malignant glioma patients. J Clin Oncol 26:2008 (May 20 suppl; abstr 9548) Abstract.
Case Reports / Journal of Clinical Neuroscience 16 (2009) 854–855
Long-term use of temozolomide: Could you use temozolomide safely for life in gliomas? Mustafa Khasraw *, David Bell, Helen Wheeler Department of Medical Oncology, Royal North Shore Hospital, Pacific Highway, St Leonards, New South Wales 2065, Australia
a r t i c l e
i n f o
Article history: Received 11 July 2008 Accepted 14 September 2008
Keywords: Temozolomide Glioma Glioblastoma multiforme
a b s t r a c t Temozolomide (TMZ) is an alkylating agent used in the management of gliomas. Although TMZ is generally safe and acute toxicity is well documented, there are limited data on long-term toxicities. We present three patients with glioma; all patients started on TMZ after having progressed following primary treatment. These patients have continued TMZ for 5 years, 7 years and 8 years respectively. So far they have had no serious side effects. We discuss these patients while raising the question of prolonged TMZ use. Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
1. Introduction The combination of surgery, radiation and temozolomide (TMZ) has become the standard therapy for patients with newly diagnosed malignant gliomas; however, no standard has emerged for recurrent disease. TMZ has been used for this group of patients either alone or in combination with other agents. The optimal dosing and duration of TMZ is still a matter of debate. We report three patients undergoing prolonged therapy with TMZ. With the limitation of this being only a retrospective report, it confirms that prolonged therapy is possible for those patients who remain sensitive to the drug. Two patients progressed on cessation of therapy and reinstitution of the drug led to long-term tumour control. 2. Case 1 A 49-year-old man presented with seizures, right-sided weakness and dysphasia. An MRI revealed an enhancing mass in keeping with a left frontal high-grade glioma. A craniotomy and brain biopsy diagnosed a gemistocytic astrocytoma. He was treated with 6 weeks of primary radiotherapy. The patient developed worsening weakness, dysphasia and headaches while we were trying to reduce dexamethasone to a dose lower than 8 mg/day. A brain MRI shortly after the radiotherapy showed a large cystic and partly solid left frontal lobe mass with significant edema and midline shift. Four months later a repeat craniotomy was undertaken with further optimal debulking. Histopathology revealed persistent gemistocytic astrocytoma with foci of incipient necrosis consistent with World health Organization (WHO) grade 3 anaplastic astrocytoma. A subsequent follow-up MRI 5 months later showed recurrent tumour, with solid and cystic components but no edema or mass effect. The patient was commenced on TMZ 200 mg/m2 for 5 days every 4 weeks. On follow-up, a progress MRI 6 months after commencing TMZ was unchanged and the patient remained clinically well. He continued TMZ. An MRI 12 months after commencing TMZ showed reduction in size of the tumour. Although we recommended that he cease TMZ treatment, the patient was reluctant to cease this agent in view of his stable condition. He continues on the day 1 to day 5 TMZ 200/m2 every 4 weeks and has not developed any bone marrow toxicity. He remains well after 5 years (62 months) * Corresponding author. Tel.: +61 2 9926 5020; fax: +61 2 9906 4150. E-mail address: [email protected] (M. Khasraw).
of TMZ treatment and his MRI has remained stable. Although he is not employed, he has normal functional capacity and an Eastern Cooperative Oncology Group (ECOG) performance status of 0. 3. Case 2 An 18-year-old man presented with a 4-week history of ataxia and dysarthria, bilateral nystagmus and partial right-sided trigeminal and facial nerve palsies. MRI showed a cystic 4 cm by 5 cm right cerebral peduncle tumor with associated edema and compression of the fourth ventricle. The histopathology from surgical debulking revealed pilocytic astrocytoma (WHO grade 1). The patient recovered postoperatively and remained stable until his gait deteriorated gradually 15 months later when an enlarging cystic recurrence was seen on follow-up MRI. Two months later he underwent a right posterior fossa craniotomy and drainage of a cerebellopontine angle cyst with the insertion of an ommaya reservoir into the cystic cavity. He recovered well and regained normal function and even returned to work as a building inspector. However, 1 year later, he had a local recurrence noted at the resection bed on MRI. He had another right posterior fossa craniotomy with re-excision of the recurrent tumor and removal of the reservoir. Histopathology reconfirmed the presence of pilocytic astrocytoma. The patient remained well and was walking unaided for another 6 months when he developed ataxia. Another cystic recurrence was noted on imaging for which he underwent a further craniotomy. Six months later the patient started to have more headaches; his general condition deteriorated and he developed a significant right-sided weakness. An MRI revealed a multicystic component and a solid area of recurrence. After four craniotomies, with decreasing time to recurrence, we thought that further adjuvant options needed to be considered. Due to his poor performance status he was not a candidate for radiotherapy. He was commenced on TMZ 200 mg/m2 for 5 days every 4 weeks. After four cycles the patient was improving clinically and TMZ was continued. The patient insisted on continuing therapy. After 3 years an MRI showed only minor enhancement at the surgical bed and the patient was convinced to cease TMZ. Unfortunately a repeat MRI 3 months after the cessation showed increased areas of enhancement in the cerebellum and brainstem. TMZ was again recommenced and since then the patient has remained both clinically and radiologically stable; however, he does have some right-sided weakness but he is able to use a walking frame outside his house. There are only minimal residual changes
Case Reports / Journal of Clinical Neuroscience 16 (2009) 854–855
on his last MRI. In 2008, after about 8 years (94 months) of TMZ chemotherapy, he remains well with a normal cognitive function but a degree of mobility limitation with an ECOG performance status of 1. 4. Case 3 A 31-year-old man presented with seizures in 1997. A CT scan showed a left frontoparietal tumor. A debulking craniotomy was undertaken. Histopathology confirmed a glioblastoma multiforme (GBM) (WHO grade 4). Adjuvant radiotherapy was administered with 60 Gy in 30 fractions followed by a stereotactic boost. He remained well for 2 years, after which he started to have seizures. He has developed a right-sided weakness. He was commenced on 12 mg of dexamethasone, carabamazepine and gabapentin. An MRI performed 4 days later revealed enhancement at the resection area consistent with recurrence of the GBM with significant edema. A fluorodeoxyglucose-positron emission tomography (FDG-PET) scan revealed increased uptake at the tumour area. Shortly afterwards he had a second craniotomy and tumor debulking. Postoperatively he remained on 8 mg of dexamethasone. Histopathology from the second craniotomy showed radiation necrosis only. He was enrolled in a clinical trial using thalidomide after the second craniotomy. However, 1 month later the patient had more seizures and his right hemiparesis deteriorated. Dexamethasone was increased to 16 mg/day. An MRI showed increase in the area of enhancement. The thalidomide dose was increased from 400 mg/day to 500 mg/day. Lack of response after 7 months of thalidomide prompted exploring other therapeutic options. TMZ 200 mg/m2 was commenced daily for 5 days every 4 weeks (as soon as it became available in Australia). The patient improved clinically, and dexamethasone was tapered. MRI appearances remained stable for 18 months and a repeat FDG-PET showed no uptake. TMZ was ceased. Unfortunately 4 months after cessation his MRI showed further progression, repeat PET showed new uptake and TMZ was recommenced. Two years later when MRI had improved and a new FDG-PET showed no uptake, another attempt to wean the TMZ was made by increasing the cycle intervals to 5 weeks. Unfortunately his MRI 7 months later showed progression of the tumor, which necessitated changing the treatment regime back to every 4 weeks. Eight years (98 months) since commencing TMZ the patient is stable with a degree of expressive dysphasia and an ECOG performance status of 1. 5. Discussion Prior to the introduction of TMZ, nitrosoureas were used for recurrent glioma. Nitrosureas cause significant marrow toxicity and other problematic side effects such as pulmonary fibrosis. TMZ is less toxic than nitrosoureas and since its introduction the treatment of gliomas and especially GBM has changed significantly. This is mainly since Stupp et al. in 2005 showed a significant 2-year survival rate of 26.5% with radiotherapy plus TMZ compared to 10.4% with radiotherapy alone.1 This trial has shown that the addition of TMZ to radiotherapy for newly diagnosed glioblastoma resulted in a statistically significant and clinically meaningful survival benefit with minimal additional toxicity. This has become the standard of care for adjuvant therapy for newly diagnosed patients with GBM. Concomitant treatment with radiotherapy plus TMZ resulted in grade 3 or 4 hematologic toxic effects in 7% of patients.1 Prolonged and severe pancytopenia after low dose continuous TMZ concurdoi:10.1016/j.jocn.2008.09.005
855
rently with cranial radiotherapy has been reported.2 There have also been reports of three patients who developed severe neutrophil dysfunction after one cycle of TMZ. It is well known that many alkylating agents can lead to secondary cancers such as acute myeloid leukemia, years after the therapy. Two cases of TMZ-related myelodysplasia and acute myeloid leukemia after 6 months to 2 years of TMZ treatment have been reported.3,4 Both these cases had previous treatment with other alkylating agents, which might have contributed. Our three patients with gliomas had progressed following surgical and radiation treatment (in the second case the patient was declined radiotherapy because of his poor performance status). These three patients have continued TMZ for 5 years, 7 years and 8 years respectively. They have, so far, had no significant hematological toxicity and no opportunistic infections. Two of the reported cases had documented disease progression upon ceasing TMZ and responded remarkably when TMZ was reintroduced. The ideal treatment length with TMZ is uncertain in this population.5,6 There has been a reported advantage to having more than 19 months of therapy, although this report has limitations, and has not been published in a peer-reviewed paper.6 However, it is generally accepted that long-term therapy with nitrosureas is not possible, given the progressive myelosuppression that ensues even in patients who respond to therapy. Many patients progress during or after first-line therapy and second-line regimens are only modestly active. Continuous dosing and dose intensification may decrease levels of O-6-methylguanine-DNA methyltransferase, which has been associated with TMZ resistance. Altering the schedule of TMZ and dose intensification may reinduce chemosensitivity.7 Significant toxicity is uncommon with TMZ, but may be significant for those at risk. Use of a clinical model to predict risk may allow for individualized dosing and management.8 TMZ is also being combined increasingly with biologic or targeted therapies and antiangiogenic agents. With the limitation of this being only a retrospective report, we suggest that unlike most patients who become resistant to TMZ at relapse, there might be a subset of patients who remain sensitive and continue to respond to this drug. Concerns about toxicity and also important health economic implications for prolonged use of TMZ will need be addressed as survival of these patients is increasing, albeit with small increments. References 1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–96. 2. Singhal N, Selva-Nayagam S, Brown MP. Prolonged and severe myelosuppression in two patients after low-dose temozolomide treatment- case study and review of literature. Neuro Oncol 2007;85:229–30. 3. Noronha V, Berliner N, Ballen KK, et al. Treatment-related myelodysplasia/AML in a patient with a history of breast cancer and an oligodendroglioma treated with temozolomide: case study and review of the literature. Neuro Oncol 2006;8:280–3.. Epub 2006 May 25. 4. Su YW, Chang MC, Chiang MF, et al. Treatment-related myelodysplastic syndrome after temozolomide for recurrent high-grade glioma. J Neurooncol 2005;71:315–8. 5. Hau P, Koch D, Hundsberger T, et al. Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. Neurology 2007;68:688–90. 6. Colman H, Hess K, Turner M, et al. Impact of duration of temozolomide therapy on progression-free survival in recurrent malignant glioma. Neuro Oncol 2002;4:368. (Abstract). 7. Perry J, Mason W, Belanger K. The temozolomide RESCUE study: A phase II trial of continuous (28/28) dose-intense temozolomide (TMZ) after progression on conventional 5/28 day TMZ in patients with recurrent malignant glioma. J Clin Oncol 26:2008 (May 20 suppl; abstr 2010) Abstract. 8. Armstrong T, Cao Y, Vera E, et al. Pharmacoepidemiology of myelotoxicity (TOX) with temozolomide (TMZ) in malignant glioma patients. J Clin Oncol 26:2008 (May 20 suppl; abstr 9548) Abstract.