Neoadjuvant Chemotherapy Approaches

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In addition to BCNU and PCV (as outlined above), numerous other chemotherapy drugs, alone and in combination, have been used for neoadjuvant treatment of high-grade astrocytomas (see Tables 24.1 and 24.2) [20-24]. Dropcho and colleagues attempted neoadjuvant intra-arterial (IA; see Chapter 17) cisplatin (75 mg/m2 every 4 weeks) in a series of 22 assessable patients with newly diagnosed high-grade astrocytomas (GBM 13, AA 9) [72]. There were five patients (23 per cent) with partial responses (PR) and five patients (23 per cent) with minor responses (MR) after IA therapy. The time to progression (TTP) ranged from 22 to 115 weeks, with a median of 39.8 weeks overall and 56.3 weeks in responders. Although hematologic, renal, and otic toxicity were mild, there were several patients with significant neurological toxicity. Other investigators have used high-dose intravenous cyclophosphamide (2 g/m2/ day for 2 doses every 28 days) as neoadjuvant treatment for 14 patients with newly diagnosed GBM [73]. There were 3 patients with CR and 3 with stable disease; TTP and survival data were limited. Toxicity was mainly hematological and included

13 admissions for neutropenia and fever, as well as transfusions for anemia and thrombocytopenia. Several reports have evaluated the use of intravenous gemcitabine, a cytosine arabinoside analog that functions as a pyrimidine antimetabolite, as a single agent or in combination for neoadjuvant chemotherapy of AA and GBM. Weller and co-workers administered gemcitabine (1000 mg/m2 on days 1, 8, and 15) for one to four monthly cycles before irradiation in a series of 21 patients with newly diagnosed GBM [74]. Of the 17 patients with evaluable residual disease, there were no CR or PR,

14 patients had stabilization of disease. The median progression-free survival and 4-month progressionfree survival rate were 11 weeks and 24 per cent, respectively. For the entire cohort, the median overall survival was 11 months. Although the regimen was safe and well tolerated, neoadjuvant single agent gemcitabine did not appear to confer any survival advantage in comparison to irradiation alone. The same group has also tested neoadjuvant gemcitabine in combination with treosulfan, a bifunctional alkylat-ing agent [75]. In this study, 17 patients with newly diagnosed GBM received gemcitabine (1000 mg/m2) and treosulfan (3500 mg/m2) on days 1 and 8 every 28 days, for up to four cycles before irradiation. The median progression-free survival and 4-month progression-free survival rate were 12 weeks and 29 per cent, respectively. For the entire cohort, the median overall survival was 12 months. The regimen was associated with prohibitive hematological toxicity, including 18 per cent with grade IV events. The addition of treosulfan did not significantly improve the survival benefit of neoadjuvant gemcitabine and was not superior to irradiation alone. Puchner and co-workers used a combination regimen consisting of tamoxifen (200 mg/day) and intravenous carboplatin (300 mg/m2 every 3 weeks x 3 cycles), followed by standard radiotherapy (5940 cGy over 6 weeks) for 50 patients with newly diagnosed GBM [76]. The median TTP was 30 weeks, with an overall median survival of 55 weeks. The 1- and 2-year survival rates were 58 and 18 per cent, respectively. It was concluded that this combination regimen did not impart any survival advantage over nitrosourea-based regimens.

Temozolomide has also been used in the neoadju-vant setting as a single agent and in combination with other cytotoxic drugs [55-61]. Friedman and associates treated 38 patients with newly diagnosed highgrade astrocytoma (GBM 33, AA 5) on a regimen of single agent TZM (200 mg/m2 x 5 days every 28 days), for up to six cycles before the onset of radiotherapy or other treatment [77]. In the GBM cohort, there were 3 patients with CR, 14 with PR, and 4 with stable disease. For AA patients, there was one brief PR and 2 with stable disease. Overall, 18 of 38 patients responded (47 per cent) to TZM in the neoadjuvant setting. Tumor responses were inversely correlated with immunohistochemical staining for MGMT. A similar study by Gilbert and colleagues treated 57 patients with newly diagnosed malignant astrocytoma (GBM 36, AA 21) with neoadjuvant TZM, for up to four cycles before proceeding to radiotherapy [78]. Almost 50 per cent of both AA and GBM patients were able to complete all four cycles of TZM before the initiation of radiation therapy. Overall, there were 22 patients with objective responses (39 per cent), including 6 patients with CR and 16 with PR. Another 18 patients (32 per cent) had stabilization of disease. The median overall and progression-free survivals for the GBM patients were 13.2 months and 3.9 months, respectively. For the AA cohort, the median overall and progression-free survivals were 23.5 months and 7.6 months, respectively. Neoadjuvant TZM was well tolerated, with infrequent episodes of grade III (28 per cent) and IV (12 per cent) toxicity. Other investigators have attempted neoadjuvant TZM for elderly patients with AA and GBM, as an alternative to external beam radiotherapy [79,80]. In one report, 86 elderly patients (70 years of age or older) with malignant astrocytomas (GBM 84,

AA 2) were treated with either radiotherapy alone (N = 54; 6000 cGy over 6 weeks) or neoadjuvant TZM (N = 32; 150-200 mg/m2/day x 5 days every 4 weeks) [79]. The median overall survival and 1-year survival rates were equivalent between the irradiation and TZM groups (4.1 versus 6.0 months and 9.26 per cent versus 11.88 per cent, respectively), with a slight advantage for the TZM treatment group which did not reach statistical significance. Temzolomide was well tolerated in this setting and appeared to be an excellent alternative to irradiation for elderly patients. A similar study by a French group evaluated the use of TZM in a cohort of 32 elderly GBM patients [80]. Objective responses were noted in nine patients (CR 0, PR 9; 31 per cent), while 12 patients had stabilization of disease. The median overall and progression-free survivals were 6.4 and 5.0 months, respectively, with a 1-year survival rate of 25 per cent.

A few reports have utilized neoadjuvant TZM in combination with other chemotherapy drugs, to determine if an additive survival benefit could be documented [55-61]. In a phase I study, TZM (200 mg/m2/day x 5 days every 4 weeks) and procarbazine (50-125 mg/m2/day x 5 days every 4 weeks, 1 hour before TZM) were administered to

28 chemotherapy-naive patients with glioma (GBM 16, AA 7) [81]. All patients received TZM alone during cycle 1 and then had escalating doses of procarbazine added for subsequent cycles. The main toxicity from combination therapy was hematological, with lymphocytopenia and thrombocytopenia noted at dosing levels 3 and 4. At dose level 4, the dose-limiting toxicity was thrombocytopenia. The recommended dose for subsequent trials was level 3, with procarbazine at 100 mg/m2/day. Objective responses were noted in 10 patients (36 per cent), nine of which had an AA (3) or GBM (6), with response duration ranging from 2 to 17+ months. Another variation of neoadjuvant combination chemotherapy used intravenous BCNU (150 mg/m2), followed after two hours by TZM (550 mg/m2) on day 1 of a 42-day cycle [82]. A total of 41 patients with anaplastic glioma were entered onto study, 33 of whom had an AA. Twenty-four patients (59 per cent) were able to complete four cycles of combined chemotherapy. Objective responses were noted in 9 patients (CR 1, PR 8;

29 per cent), all of which had AA histology. The regimen was associated with significant hematologi-cal toxicity, with grade III/IV granulocytopenia and thrombocytopenia noted in 21 and 46 per cent of patients, respectively. Overall, neoadjuvant TZM and BCNU was quite toxic and did not appear to provide a survival benefit in comparison to singleagent chemotherapy approaches. Neoadjuvant TZM

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