|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 33 (November 20), 2006: pp. 5271-5276 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.7272 Irinotecan Plus Temozolomide for Relapsed or Refractory Neuroblastoma
From the Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY Address reprint requests to Brian H. Kushner, MD, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: kushnerb{at}mskcc.org
Purpose To report on an irinotecan and temozolomide regimen for neuroblastoma (NB). Quality of life and minimizing toxicity were major considerations. Patients and Methods The plan stipulated 5-day courses of irinotecan 50 mg/m2 (1-hour infusion) and temozolomide 150 mg/m2 (oral) every 3 to 4 weeks, with a pretreatment platelet count more than 30,000/µL. Granulocyte colony-stimulating factor was used when the absolute neutrophil count was less than 1,000/µL. Results Forty-nine NB patients received 1 to 15 courses (median, 5). Gastrointestinal and myelosuppressive toxicities were readily managed. Lymphocyte responses to phytohemagglutinin after 2 to 10 courses (median, 3.5) were normal in 10 of 10 patients treated after nonimmunosuppressive therapy, and normalized in five of seven patients first treated less than 2 months after high-dose alkylators. Of 19 patients treated for refractory NB and assessable for response, nine showed evidence of disease regression, including two complete responses and seven objective responses. Of 17 patients treated for progressive disease, three showed evidence of disease regression, including one partial response and two objective responses. Multiple courses entailed no cumulative toxicity and controlled disease for prolonged periods in many patients, including some who were unable to complete prior treatments because of hematologic, infectious, cardiac, or renal problems. Conclusion This regimen has anti-NB activity, spares vital organs, is feasible with poor bone marrow reserve, causes limited immunosuppression, and allows good quality of life.
Standard treatment for high-risk neuroblastoma (NB) includes dose-dense or dose-intensive induction, as well as myeloablative chemotherapy regimens using alkylating agents, platinum compounds, and topoisomerase II inhibitors, plus complex surgery and radiotherapy. Persistence or relapse of NB occurs in more than 50% of patients.1,2 First-line retrieval treatments include cyclophosphamide plus the topoisomerase I inhibitor topotecan3 and targeted radiotherapy with [131I]metaiodobenzylguanidine (MIBG),4 but responses are usually incomplete or transient. Subsequent treatment options may be limited because of deleterious effects on bone marrow (BM) reserve, kidney function, and cardiac status from the extensive prior therapy. In the above difficult clinical settings—resistant NB after multimodality therapy, poor hematologic status, impaired function of major organs—we have tried a 5-day irinotecan and temozolomide regimen. We previously described the use of irinotecan alone5 or with high-dose cyclophosphamide6 in patients with resistant NB. The rationale for choosing irinotecan, which is a topoisomerase I inhibitor, included its efficacy against human NB xenografts7-9; cytotoxicity at relatively nonmyelosuppressive doses, as well as manageable nonhematologic toxicity (diarrhea)10-21; and evidence that it is less affected by P-glycoprotein multidrug resistance compared with topoisomerase II inhibitors, such as doxorubicin and etoposide.22 Its mechanism of action—mainly S phase specific obstruction of DNA replication—supported combined use with an alkylating agent as a strategy for increasing tumor-cell kill. Temozolomide is an alkylating agent that has recently attracted much attention because of its activity against brain tumors23 and melanoma,24 excellent oral bioavailability,25,26 efficient penetration of the blood-brain barrier,27,28 and modest toxicity. We now describe the antitumor effects and the toxicity, including possible immunosuppression,29-31 of 5-day courses of irinotecan and temozolomide in NB patients. In the sole prior detailed reports on combined use of these agents in children,32,33 temozolomide was taken orally for 5 days as in our regimen but at 33% lower dosage, and irinotecan was administered intravenously (IV) in a prolonged schedule (5 days/wk, for 2 weeks) with a total dosage 25% lower than in our regimen.
Memorial Sloan-Kettering Cancer Center (New York, NY) patients with refractory or relapsed NB received one or more 5-day courses of irinotecan 50 mg/m2/d infused IV over 1 hour (250 mg/m2/course) plus temozolomide 150 mg/m2/d (750 mg/m2/course) taken orally. Informed written consents for treatment were obtained after guardians (or, as appropriate, patients) understood its investigational nature, the known adverse effects of each agent, and the possibility of unforeseen severe toxicities. All patients were approved for inclusion in this report by the institutional review board. Treatments were outpatient, courses were to start every 3 to 4 weeks, the pretreatment platelet counts were more than 30,000/µL (untransfused), and granulocyte colony-stimulating factor was used (single doses) only when the absolute neutrophil count decreased to less than 1,000/µL. Because of expected diarrhea, loperamide usage was explained to family/patients. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria.
Disease status was assessed by computed tomography (CT; or magnetic resonance imaging [MRI]), [123I]MIBG scan, urine catecholamines, and bilateral BM biopsies and aspirates. These tests were generally carried out after every two to three courses, but at least one of these monitoring studies was done more often. The International Neuroblastoma Response Criteria (INRC)34 were used: complete response (CR), no evidence of NB; very good partial response, volume of primary mass reduced by more than 90%, no evidence of distant NB (including normal MIBG) except for skeletal residua, catecholamines normal; partial response (PR), more than 50% decrease in measurable disease and
Patient Characteristics All 49 patients (male:female, 23:26) had high-risk stage four NB. Refractory or relapsed NB was biopsy-proven in 40 patients, and evidenced by new or persistent MIBG abnormalities in nine patients. They received one to 15 courses (median, 5) of irinotecan and temozolomide, were 2.3 to 25.9 years old (median, 5.5), and were 0.3 to 17.1 years (median, 2.5) from diagnosis. Commonly used prior treatments included irinotecan by some other schedule or with another agent (n = 21), hematopooietic stem-cell transplantation (n = 30), 13-cis-retinoic acid (n = 30), topotecan (n = 40), high-dose cisplatin or carboplatin (n = 43), and high-dose cyclophosphamide (n = 48). Three patients had previously received temozolomide.
Response The 19 patients assessable for response of refractory NB (Table 1) included nine who had incomplete responses (eight SD, one PR) to induction therapy and 10 who had incomplete responses (eight SD, two PR) to salvage therapy for a first relapse (n = 5) or a second or later relapse (n = 5). Among these 19 patients, eight had SD (three to seven courses) and then changed therapy, two current patients have SD (eight and 15 courses to date), and nine showed responses, as follows. Two patients had CR: one patient who, after 21 months of various therapies, achieved CR by resolution of BM disease (after two courses, and ultimately received 12 courses before proceeding to maintenance with 13-cis-retinoic acid), and one patient who achieved CR by resolution of BM disease and normalization of MIBG scan (after two courses, and then proceeded to high-dose consolidative chemotherapy). Seven patients had SD (after two to seven courses) by INRC but demonstrated objective responses: two patients had improved findings in MIBG scans, CT/MRI studies, and urine catecholamine levels; two patients had CR in BM but persistence of epidural disease and skeletal MIBG positivity, respectively; two patients had PR in BM but persistence of epidural disease and more than 50% decrease in urine catecholamine levels, respectively; and one patient had a marked decrease in the number and size of liver metastases plus normalization of MIBG scan.
Two of 17 patients treated for PD (Table 1) received irinotecan and temozolomide as the initial treatment of a second relapse: one patient had SD by INRC but showed an objective response (recurrent tumor in hilum decreased < 50%) and one patient's widespread NB progressed further. Among the 15 patients treated for PD that occurred during salvage therapy, eight had further PD after one to three courses, four had PD after four to six courses, and one current patient has SD with five courses to date. Two patients had disease regressions: one patient whose NB had been progressing after 6 months of chemotherapy for a post-transplant relapse had PR (six courses, with near normalization of heavily involved BM, extensively abnormal MIBG scan, and very high urine catecholamine levels), and one patient had SD by INRC but demonstrated an objective response as evidenced by rapid resolution of bony pain, normalization of rising serum lactate dehydrogenase (510 U/L to 186 U/L; normal < 200 U/L), and a significant decrease in urine catecholamine levels.
Toxicity Myelosuppression was manageable and clinically insignificant. In patients with pretreatment platelet counts more than 100,000/µL, courses could be started every 3 weeks. In patients with pretreatment platelet counts of 32,000 to 85,000/µL, courses could be started every 3 to 5 weeks. Blood-borne bacterial infections were limited to Staphylococcus epidermidis in two patients and Stenotrophomonas maltophilia in one patient. The sole opportunistic infection was cytomegalovirus in blood. However, that event occurred after only one course in a 4-year-old girl whose immediate prior treatment included high-dose cyclophosphamide (140 mg/kg), which is strongly immunosuppressive. Lymphocyte responses to phytohemagglutinin (PHA) were tested in subsequent patients (Table 2). After two to 10 courses (median, 3.5), results were normal in 10 of 10 patients who were first treated with irinotecan and temozolomide after nonimmunosuppressive chemotherapy, and results normalized in five of seven patients who were first treated less than 2 months after receiving strongly immunosuppressive doses of cyclophosphamide (140 mg/kg or approximately 4,200 mg/m2) or ifosfamide (10 g/m2). Of the five patients who had low PHA responses when first tested after that high-dose alkylator therapy plus three to five courses of irinotecan and temozolomide, four patients were retested after additional courses of irinotecan and temozolomide, and the PHA responses normalized in three patients and improved in one patient (Table 2).
Five-day courses of irinotecan and temozolomide in a large series of heavily treated NB patients had manageable adverse effects and no unexpected toxicities. The regimen was compatible with normal age-appropriate activities. Ease and rapidity of administration, plus little emetogenic effect, allowed outpatient treatment. When they occurred, gastrointestinal symptoms were generally self-limited, of short duration, or responsive to standard medications. Courses could be started every 3 weeks in patients with good BM reserve and every 3 to 5 weeks in patients with pre-existing grade 2 to 3 hematologic toxicity. Intermittent use of granulocyte colony-stimulating factor probably helped reduce infectious risks and may have resulted in less cytokine-associated suppression of platelet production than that seen with daily injections. Multiple courses entailed no cumulative toxicity and controlled disease for prolonged periods in many patients, including some who were unable to complete prior treatment programs because of poor BM reserve, infection, or injury to vital organs (kidney, heart). Overall, of the 36 patients assessable for response, 12 patients (33%) had disease regressions, including three patients (8%) with CR or PR, and nine patients with objective responses (Table 1). Schedule and dosing were based on prior studies of each agent alone. Pediatric phase I studies of temozolomide identified 200 to 215 mg/m2/d for 5 days every 4 weeks as the maximum tolerated dose.25,35 For combined use with irinotecan, we lowered the daily temozolomide dosage to 150 mg/m2/d for 5 days, which has shown activity against brain tumors,30,36-38 but higher dosing may be possible in patients with good hematologic status (ie, platelet count > 100,000/µL). The 5-day timing accorded well with our favorable prior experience using 5-day courses of irinotecan every 3 to 4 weeks, either as monotherapy5 or with high-dose cyclophosphamide.6 Irinotecan has shown antitumor activity when used in a variety of schedules, including one dose every 3 weeks,17,19 weekly doses,15,21 or daily doses for 3 to 10 days every 3 to 4 weeks.10-14,16,18,20,39 In the current study, as well as in our past studies,5,6 we chose a 5-day schedule because of its convenience for patients, its promising antitumor activity,8,11,12,16 and its approximation to the 10-day schedule associated with anti-NB effects in an animal model.9 We also aimed for similar timing of the myelosuppressive effects of each agent. We picked an irinotecan dosage of 250 mg/m2/course because of its overlap with dosages that produced favorable results in patients with NB or other poor-prognosis solid tumors.10-12,14,16 An elegant, very recent phase I and pharmacokinetic study of oral irinotecan by a prolonged schedule (5 days/wk, for 2 weeks) showed that higher monotherapy dosing is possible with antibiotic-induced alteration of intestinal flora, which diminishes irinotecan's diarrheal toxicity.39 In that study, daily usage of cefixime allowed escalation of oral irinotecan to 60 mg/m2/d, which yielded serum levels of the cytotoxic metabolite in the same range as those achieved with 20 mg/m2/d by the IV route. While gastrointestinal toxicity has been a vexing issue with prolonged schedules,10,14,32 that problem has not been clinically significant with 5-day courses using higher daily IV doses of irinotecan (50 mg/m2), either in our experience or in the experience of others.12,16 Nevertheless, the efficacy of cefixime at ameliorating the diarrheal toxicity of irinotecan taken orally offers the possibility that antibiotic usage may also allow higher IV dosing of irinotecan which may translate into better antitumor activity. As regards temozolomide, one strategy for augmenting its antitumor activity involves use of O6-benzylguanine which blocks an enzyme that can repair temozolomide-mediated DNA damage.40 In a pediatric phase I trial,41 O6-benzylguanine and relatively low temozolomide dosages (ie, 55 to 100 mg/m2/d for 5 days every 4 weeks) produced responses in patients with recurrent or refractory brain tumors. The results were deemed encouraging in view of the poor response rates of pediatric high-grade gliomas to temozolomide at standard dosages (ie, 200 mg/m2/d for 5 days).25,35,42 In addition to its modest myelosuppressive effects, the 5-day irinotecan and temozolomide regimen had little immunosuppressive activity, as shown by the normal PHA responses in eight of eight patients whose immediate prior therapy was not strongly immunosuppressive and by the return to normal PHA results in five of seven patients whose immediate prior therapy included high-doses of immunosuppressive alkylating agents (Table 2). These PHA studies were prompted by cytomegalovirus infection in one of our patients (although prior treatment with high-dose cyclophosphamide was the likely critical predisposing factor) and by concerns about excessive immunosuppression in adults treated with temozolomide 75 mg/m2/d for 6 weeks every 8 weeks29 or with temozolomide 150 mg/m2/d in a 1-week on/1-week off schedule.30,31 Our findings allowed us to discontinue prophylaxis against Pneumocystis carinii, another step towards better quality of life. However, in a given patient the prophylaxis should continue until a satisfactory PHA response is documented. Low-dose oral etoposide also entails modest immunosuppression,43 but we know of no reports on this issue with other salvage therapies commonly used in NB patients.3,4,32 To our knowledge, immunosuppression among NB patients has been described for only one commonly used salvage regimen—namely, low-dose oral etoposide, which, like the 5-day irinotecan and temozolomide regimen, produced no significant immunosuppression.43 Regarding NB, marked patient heterogeneity and small numbers of subjects confound efforts to compare results of irinotecan-temozolomide with past experience using either agent alone at slightly higher dosages or by other schedules. Thus, past reports of monotherapy with irinotecan for NB range from one or two cases18,20,21 to five to 26 patients10,12,13,17,39 and there is only one report of monotherapy with temozolomide in NB patients.44 Nevertheless, support for their combined use comes from (1) the possibility of better antitumor activity through temozolomide-induced suppression of DNA repair mechanisms that can block irinotecan cytotoxicity45; (2) a preclinical study that showed significant therapeutic synergy when tumor xenografts were treated with noncurative doses of each agent46; (3) pediatric clinical trials in which gratifying antitumor activity was observed when these agents were used at the relatively low dosages of irinotecan 20 mg/m2/d for 10 days (200 mg/m2/course) and temozolomide 100 mg/m2/d for 5 days (500 mg/m2/course)32,33; (4) the absence of pharmacokinetic interaction between these agents32,46; and (5) their nonoverlapping toxicities. Additional considerations that favor using irinotecan and temozolomide in NB patients include the efficacy of each agent against relatively chemoresistant neural tumors,15,30,36,37 evidence that each agent acts as a radiation sensitizer,23,38,47,48 and the need for regimens to prevent or treat NB relapse in the CNS.49 Other schedules are under study in adults.50 Temozolomide, like other alkylating agents, may be leukemogenic.51 We conclude that this regimen has anti-NB activity, does not exacerbate preexisting toxic effects on vital organs from extensive prior therapy, is feasible in patients with poor hematologic status, and allows good quality of life. It lends itself to use in the setting of relapsed or refractory high-risk NB, including as maintenance therapy for second or greater remission. However, the 8% major response rate suggests that it cannot replace dose-intensive therapy using the traditional alkylating agents (cyclophosphamide, ifosfamide) and platinum compounds for induction in newly diagnosed patients.
The authors indicated no potential conflicts of interest.
Supported by grants from the National Cancer Institute (CA61017, CA72868), Bethesda, MD; Hope St Kids, Alexandria, VA; the Justin Zahn Fund, New York, NY; the Katie's Find A Cure Fund, New York, NY; and the Robert Steel Foundation, New York, NY. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341 : 1165 -1173, 1999 2. Berthold F, Boos J, Burdach S, et al: Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: A randomized controlled trial. Lancer Oncol 6 : 649 -658, 2005 3. Saylors RL, Stine KC, Sullivan J, et al: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: A Pediatric Oncology Group phase II study. J Clin Oncol 19
: 3463
-3469, 2001 4. Kang TI, Brophy P, Hickeson M, et al: Targeted radiotherapy with submyeloablative doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma. J Pediatr Hematol Oncol 25 : 769 -773, 2003[CrossRef][Medline] 5. Kushner BH, Kramer K, Modak S, Cheung N-KV: Five-day courses of irinotecan as palliative therapy for patients with neuroblastoma. Cancer 103 : 858 -862, 2004 6. Kushner BH, Kramer K, Modak S, et al: Camptothecin analogs (irinotecan or topotecan) plus high-dose cyclophosphamide as preparative regimens for antibody-based immunotherapy in resistant neuroblastoma. Clin Cancer Res 10
: 84
-87, 2004 7. Komuro H, Li P, Tsuchida Y, et al: Effects of CPT-11 (a unique DNA topoisomerase I inhibitor) on a highly malignant xeno-transplanted neuroblastoma. Med Pediatr Oncol 23 : 487 -492, 1994[Medline] 8. Vassal G, Terrier-Lacombe MJ, Bissery MC, et al: Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts. Br J Cancer 74 : 537 -545, 1996[Medline] 9. Thompson J, Zamboni WC, Cheshire PJ, et al: Efficacy of systemic administration of irinotecan against neuroblastoma xenografts. Clin Cancer Res 3 : 423 -431, 1997[Abstract] 10. Furman WL, Stewart CF, Poquette CA, et al: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17
: 1815
-1824, 1999 11. Rosoff PM, Bayliff S: Successful clinical response to irinotecan in desmoplastic small round blue cell tumor. Med Pediatr Oncol 33 : 500 -503, 1999[CrossRef][Medline] 12. Blaney S, Berg S, Pratt C, et al: A phase I study of irinotecan in pediatric patients: A Pediatric Oncology Group study. Clin Cancer Res 7 : 3237 , 2001 13. Mugishima H, Matsunaga T, Keiko Y, et al: Phase I study of irinotecan in pediatric patients with malignant solid tumors. J Pediatr Hematol Oncol 24 : 94 -100, 2002[CrossRef][Medline] 14. Cosetti M, Wexler LH, Calleja E, et al: Irinotecan for pediatric solid tumors: The Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol 24 : 101 -105, 2002[CrossRef][Medline] 15. Turner CD, Gururangan S, Estwood J, et al: Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: The Duke experience. Neuro Oncol 4 : 102 -108, 2002[Abstract] 16. Katzenstein HM, Rigsby C, Shaw PH, et al: Novel therapeutic approaches in the treatment of children with hepatoblastoma. J Pediatr Hematol Oncol 24 : 751 -755, 2002[CrossRef][Medline] 17. Vassal G, Doz F, Frappaz D, et al: A phase I study of irinotecan as a 3-week schedule in children with refractory or recurrent solid tumors. J Clin Oncol 21
: 3844
-3852, 2003 18. Shitara T, Shimada A, Tsuchida Y, et al: Successful clinical response to irinotecan in relapsed neuroblastoma. Med Pediatr Oncol 40 : 126 -128, 2003[CrossRef][Medline] 19. Palmer RD, Williams DM: Dramatic response of multiply relapsed hepatoblastoma to irinotecan. Med Pediatr Oncol 41 : 78 -80, 2003[CrossRef][Medline] 20. Inagaki J, Yasui M, Sakata N, et al: Successful treatment of chemoresistant stage 3 neuroblastoma using irinotecan as a single agent. J Pediatr Hematol/Oncol 27 : 604 -606, 2005[CrossRef][Medline] 21. Bomgaars LB, Kerr J, Berg S, et al: A phase I study of irinotecan administered on a weekly schedule in pediatric patients. Pediatr Blood Cancer 46 : 50 -56, 2006[CrossRef][Medline] 22. Pommier Y, Gupta M, Valenti M, et al: Cellular resistance to camptothecins. Ann NY Acad Sci 803 : 60 -73, 1996[Medline] 23. DeAngelis LM: Chemotherapy for brain tumors: A new beginning. N Engl J Med 352
: 1036
-1037, 2005 24. Gajewski TF: Temozolomide for melanoma: New toxicities and new opportunities. J Clin Oncol 22
: 580
-581, 2004 25. Estlin EJ, Lashford L, Ablett S, et al: Phase 1 study of temozolomide in pediatric patients with advanced cancer. Br J Cancer 78 : 652 -661, 1998[Medline] 26. Baker SD, Wirth M, Statkevich P, et al: Absorption, metabolism, and excretion of 14C-Temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res 5
: 309
-317, 1999 27. Agarwala SS, Kirkwood JM: Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. Oncology 5 : 144 -151, 2000 28. Stupp R, Osermann S, Leyvraz S, et al: Cerebrospinal fluid levels of temozolomide as a surrogate marker for brain penetration. Proc Am Soc Clin Oncol 20 : 59a , 2001 (abstr 232) 29. Su YB, Sohn S, Krown SE, et al: Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: A toxicity with therapeutic implications. J Clin Oncol 22
: 610
-616, 2004 30. Wick W, Weller M: How lymphotoxic is dose-intensified temozolomide? The glioblastoma experience. J Clin Oncol 23
: 4235
-4236, 2005 31. Kulka MH, Stuart K, Enzinger PC, et al: Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24
: 401
-406, 2006 32. Wagner LM, Crews KR, Iacono LC, et al: Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res 10
: 840
-848, 2004 33. Wagner LM, McAllister N, Goldsby RE, et al: Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer (in press) 34. Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11
: 1466
-1477, 1993 35. Nicholson HS, Krailo M, Ames MM, et al: Phase 1 study of temozolomide in children and adolescents with recurrent solid tumors: A report from the Children's Cancer Group. J Clin Oncol 16
: 3037
-3043, 1998 36. Yung AWK, Prados MD, Yaya-Tur R, et al: Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17
: 2762
-2771, 1999 37. Kuo D, Weiner H, Wisoff J, et al: Temozolomide is active in childhood, progressive, unresectable, low-grade gliomas. J Pediatr Hematol Oncol 25 : 372 -378, 2003[CrossRef][Medline] 38. Stupp R, Warren P, Mason W, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352
: 987
-996, 2005 39. Furman WL, Crews KR, Billups C, et al: Cefixime allows greater dose escalation of oral irinotecan: A phase I study in pediatric patients with refractory solid tumors. J Clin Oncol 24
: 563
-570, 2006 40. Friedman HS, Keir S, Pegg AE, et al: O6-benzylguanidine-mediated enhancement of chemotherapy. Mol Cancer Ther 1
: 943
-948, 2002 41. Warren KE, Aikin AA, Libucha M, et al: Phase 1 study of O6-benzylguanine and temozolomide administered daily for 5 days to pediatric patients with solid tumors. J Clin Oncol 23
: 7646
-7647, 2005 42. Lashford LS, Thiesse P, Jouvet A, et al: Temozolomide in malignant gliomas of childhood: A United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study. J Clin Oncol 20
: 4684
-4691, 2002 43. Kushner BH, Kramer K, Cheung N-KV: Oral etoposide for refractory and relapsed neuroblastoma. J Clin Oncol 17
: 3221
-3225, 1999 44. Donfrancesco A, Jenkner A, Castellano A, et al: Ifosfamide/carboploatin/etoposide (ICE) as front-line, topotecan/cyclophosphamide as second-line and oral temozolomide as third-line treatment for advanced neuroblastoma over one year of age. Acta Paediatr Supplement 445 : 6 -11, 2004 45. Pourquier P, Waltman JL, Urasaki Y, et al: Topoisomerase I-mediated cytotoxicity of N-methyl-N'-nitro-N-nitroguanidine: Trapping of topoisomerase I by the O6-methylguanine. Cancer Res 61
: 53
-58, 2001 46. Houghton PJ, Stewart CF, Cheshire PJ, et al: Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models. Clin Cancer Res 6
: 4110
-4118, 2000 47. Rich TA, Kirichenko AV: Camptothecin radiation sensitization: Mechanisms, schedules, and timing. Oncology 12 : 114 -120, 1998[Medline] 48. van Rijn J, Heimans JJ, van den Berg J, et al: Survival of human glioma cells treated with various combination of temozolomide and x-rays. Int J Radiat Oncol Biol Phys 47 : 779 -784, 2000[CrossRef][Medline] 49. Kramer K, Kushner BH, Heller G, et al: Neuroblastoma metastatic to the central nervous system: The Memorial Sloan-Kettering Cancer Center experience and a literature review. Cancer 91 : 1510 -1519, 2001[CrossRef][Medline] 50. Jones SF, Gian VG, Greco FA, et al: Phase I trial of irinotecan and temozolomide in patients with solid tumors. Oncology 17 : 41 -45, 2003 (suppl)[Medline] 51. Su Y-W, Chang M-C, Chiang M-F, et al: Treatment-related myelodysplastic syndrome after temozolomide for recurrent high-grade glioma. J Neuro-Oncol 71 : 315 -318, 2005[CrossRef][Medline] Submitted March 23, 2006; accepted September 6, 2006.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
1 positive BM site; mixed response, more than 50% decrease of any lesion with less than 50% decrease in any other; no response, less than 50% decrease but less than 25% increase in any lesion; and progressive disease (PD), new lesion or more than 25% increase in an existing lesion. We classified mixed response and no response as stable disease (SD). 
