Temozolomide with Radiotherapy for the Treatment of Malignant Gliomas, Center Experience

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1 Temozolomide with Radiotherapy for the Treatment of Malignant Gliomas, Center Experience *Ehab Abdou and **Mohamed Gaafar *Department of Radiation Oncology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt **Public Health Department, Faculty of Medicine, Munofia University, Munofia, Egypt Abstract Background: Temozolomide (TMZ), a proven effective alkylating agent that shown better results in the treatment of patients with malignant gliomas when used as single modality treatment or when concurrently used in combination with radiation therapy. 1 Purpose: This is a phase II retrospective study aim to determine the effects of concomitant plus sequential TMZ with radiotherapy in patients with newly diagnosed malignant gliomas. MATERIAL & METHODS In our retrospective study, between 2007 and 2009 twenty patients data were collected all patients had pathologically confirmed anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) who received TMZ concomitant with radiotherapy followed by adjuvant TMZ. Patients received TMZ as 75 mg/m2 orally daily concurrently with radiotherapy then 150 mg / m2 orally for 5 days every 28 days for six cycles after radiotherapy. Radiotherapy was delivered as 60 Gy in 30 fractions to the tumor site with a 2 to 3 cm margin. The primary end points included response rate and toxicity. Secondary end points were progression-free survival (PFS) and overall survival (OS) at twelve months. RESULTS KEY WORDS: Temozolomide, radiotherapy, malignant gliomas. Male patients represented the majority of patients 17 patients (85%). Thirteen patients were 40 years, half of the patients enjoyed Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0-1 and about one half (10 patients i.e. 50%) had AA. Correspondence to: Ehab Abdou, Department of Radiation Oncology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt. 149

2 Ehab Abdou Surgical approach was hetrogenous in those studied patients. Near total excision was done for half of them while 7 patients had partial excision and 3 patients had biopsy only. No complete response rate (RR) was seen but the overall RR was 40%. Analysis of RR according to prognostic factors showed significantly higher RR only among patients 40 years in cmparison to other age groups. There was improvement of PS in 40 % of patients (8 patients). Hematological toxicity was the main feature in the treatment toxicity profile as mild to moderate in severity. Median times to disease progression was 6.9 months and PFS rates was 35% at 12 months. Median survival was 12 months and OS rates 65% at 12 months. CONCLUSION TMZ combined with radiotherapy (concomitantly and sequentially) is well tolerated and it is confirmed to give a better tumor control in patients with malignant gliomas. INTRODUCTION In the year 2008, an estimated 21,810 new cases of primary brain and other nervous system neoplasms will be diagnosed in the United States. These tumors will be responsible for approximately 13,070 deaths. The incidence of primary malignant brain tumors has been increasing over the last 30 years, especially in elderly persons (rates are increasing at about 1.2% each year). Primary brain tumors range from pilocytic astrocytomas (which are very uncommon, noninvasive, and surgically curable) to glioblastoma multiforme, the most common intraparenchymal brain tumor in adults, which is highly invasive and virtually incurable. Because of this marked heterogeneity, the prognostic features and treatment options for brain tumors must be carefully reviewed for each patient. Several important principles guide surgical and radiation therapy (RT) for adults with primary brain tumors. 2 Regardless of tumor histology, neurosurgeons generally provide the best outcome for their patients if they remove as much tumor as possible, keep surgical morbidity to a minimum, and ensure an accurate diagnosis. Decisions regarding aggressiveness of surgery for a primary brain tumor are complex and depend on the (1) age and performance status (PS) of the patient; (2) proximity to eloquent areas of the brain; (3) feasibility of decreasing the mass effect with aggressive surgery; (4) resectability of the tumor (including the number and location of lesions); and (5) in patients with recurrent disease, the time since the last surgery. The surgical options include stereotactic biopsy, open biopsy or debulking procedure, subtotal resection, or gross total tumor resection where feasible. The pathologic diagnosis is critical and often difficult to determine accurately; therefore, as much tissue as possible should be delivered to the pathologist. 3 In adults, the most common pathological types are anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). The standard management of malignant gliomas involves cytoreduction through surgical resection, when feasible, followed by radiotherapy (RT) with or without adjuvant chemotherapy. Despite this multidisciplinary approach, the prognosis for patients with GBM remains poor. The median survival rates for GBM are typically in the range of 9 to 12 months, with 2-year survival rates in the range of only 8% to 12 %. 4 Many chemotherapeutic agents were used to enhance the results of AA and GMF treatment. Nitrosoureas were the main chemotherapeutic agents used in the treatment of malignant brain tumors; however, they have shown only modest antitumor activity. Although frequently prescribed in the United States, the benefit of adjuvant chemotherapy with single-agent carmustine (BCNU) or lomustine or the combination regimen procarbazine, lomustine, and vincristine has never been conclusively demonstrated. A meta- analysis on published data suggested a possible benefit of adjuvant chemotherapy, mainly for AA. 5 In a large randomized trial conducted by the British Medical Research Council, adjuvant combination regimen procarbazine, lomustine, and vincristine chemotherapy detected no benefit to AA or GBM patients, with a median survival of only 10 months. The absence of chemotherapeutic efficacy in this and other clinical trials may be due in part to the inability of these agents to sufficiently penetrate the blood-brain barrier. 6 TMZ is an alkylating agent that has demonstrated activity initially in recurrent gliomas. After oral administration, temozolomide is rapidly absorbed with almost 100% bioavailability. It readily crosses the bloodbrain barrier and achieves effective concentration in the CNS with a reported plasma CSF ratio of approximately 30% to 40 %. Resistance of TMZ is mediated in part through O 6 -alkylguanine DNA alkyltransierase (GTV). This repair enzyme, also known as methylguanine-dna methyuransterase, was found to be a major determinant of 150

3 Temozolomide with Radiotherapy for the Treatment of... TMZ cytotoxicity in vitro; continuous exposure to TMZ leads to depletion of this enzyme. Therefore, a continuous administration schedule for TMZ has been investigated and a dose of 75 mg/m 2 daily for 6 to 7 weeks seems safe. 7 The rationale for combining TMZ with radiotherapy is based on preclinical data suggesting additive or perhaps synergistic activity. TMZ with concurrent irradiation demonstrated additive cytotoxicity against the gliobastoma cell line with low AGT expression, whereas this effect was absent in a colorectal cell line that expresses high levels of AGT. Van Rijn et al investigated prolonged temozolomide exposure followed by single-dose and fractionated irradiation in two glioma cell lines. No enhancement of cytotoxicity could be demonstrated in the U251 cell line, but prolonged exposure to TMZ and fractionated irradiation enhanced cytotoxicity in the D384 cell line. It has been shown that TMZ induces a G 2 -M arrest in glioma cells, thus synchronizing the cell cycle in a radiosensitive phase. 8 Thrombocytopenia and neutropenia are the most common dose-limiting toxicities, with grade 3 or 4 myelosuppression occurring in less than 10% of treated patients. Of particular interest for the treatment of patients with previous exposure to nitrosoureas is that TMZ-induced myelosuppression is reversible and does not seem to be cumulative. In many reported multicenter phase II trial, TMZ demonstrated efficacy in both recurrent AA and GBM. In patients with AA, TMZ treatment after first relapse resulted in objective responses in 35% of patients. Another study compared TMZ with procarbazine in recurrent GBM, both median progression-free survival (PFS) (12.4 v 8.32 weeks; P=.0063) and 6- months OS (60% v 44%; P=.019) were improved in patients treated with TMZ. 9 This is a phase II retrospective study that was carried out at Bahrain Oncology Department to determine effects of concomitant plus sequential TMZ with radiotherapy in patients with malignant gliomas. PATIENTS AND METHODS Patient Selection Between May 2007 and April 2009, data of 20 patients were collected and those eligible to the study were included. Eligibility criteria 1. Pathologically confirmed AA or GBM. 2. Surgical management to be near total excision, debunking surgery or biopsy 3. Patients age ranged between years old. 4. ECOG performance status score Normal renal, liver, and hematological profile. 6. No prior radiation therapy or chemotherapy. Pretreatment Evaluation Initial evaluation and work-up included patient history, clinical examination, laboratory investigations (blood count, liver and renal function tests) and computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain. Treatment TMZ as 75 mg/m2 orally daily concurrently with radiotherapy then 150 mg / m2 orally for 5 days every 28 days for six cycles after radiotherapy. Radiotherapy The PTV was determined by contrast enhanced lesion and the surrounding edema plus a minimum margin of 2-cm (as shown in the pre-operative C.T. scan or MRI). Radiotherapy started 4 week from surgery. LINAC (VARIAN) was used to deliver the dose as 2 Gy daily fractions, 5 days/week. The initial irradiation volume included the. This volume was irradiated to a dose of 50 Gy, then reduced to the contrast enhancing lesion plus 2 cm and the dose was increased up to 60 Gy. Patients were treated in supine position but other appropriate positions were possible. Appropriate arrangement and number of fields, depending on tumor size and location were used. Many dose modifiers were used as wedge-pair of fields, 3 fields or multiple fields. Chemotherapy Patients received TMZ (75 mg/m 2 orally daily all through the radiotherapy course and then for 6 cycles after radiotherapy as 150 mg /m2 daily on Day 1-5 every 151

4 Ehab Abdou 4 weeks. Patients were instructed to fast during at least one hour before and one hour after administration of TMZ, and to swallow the whole capsule in rapid succession without chewing them. Antiemetics were given prior to treatment. Laboratory investigations (CBC, liver and kidney functions) were done before each cycle of chemotherapy. Treatment discontinued if unacceptable toxicity developed or disease progression was observed. During and after Treatment Patients were evaluated weekly during treatment, monthly for 6 months and every two months thereafter. The primary end points included response rate and toxicity. Secondary end points were progression-free survival (PFS) and overall survival (OS) at twelve months. Evaluation for response was performed 2 months after end of treatment. Tumor response and treatment related toxicities were evaluated according to WHO criteria. Toxicity and Response Response was assessed according to WHO criteria 10 while toxicity to treatment was reported according to WHO and EORTC toxicity criteria. 11 Statistical Analysis Statistical package for social sciences (SPSS) version 16 was used for data base construction and analysis. Quantitative variables were summarized using mean and SD, median minimum and maximum values. Qualitative data were summarized using frequencies and percentage. The starting point was the date of diagnosis for survival and response while it was the end of treatment for the time to relapse. Immediate local failure was counted whenever residual tumor is detected. Survival analysis was done using Kaplan- Meier, comparisons between survival curves was done using Log-rank test. Differences were considered significant when p was 0.05 and highly significant when p RESULTS Patient Characteristics A total of 20 patients were included in the study. The treatment was completed in all patients. There were 14 patients (70%) 40 years, 6 patients (30%) > 40 years, while 18 patients were males (90%) and 2 patients were females (10%). The mean age was 44.4 ± 6.6 (Range 26-66). Eleven patients (55%) had ECOG performance status score 0-1, and 9 patients (45%) had ECOG performance status score 2. AA was reported in 55% of patients while GBM was reported in 45% of patients. Three patients (15%) had only biopsy, nine patients (45%) had partial excision and 8 patients (40%) had near total excision. Table (1) shows patients characteristics. Characteristics No (n=20) % Age (years) > Range Mean ± SD 44.4 ± 6.6 Sex Male Female 2 10 Performance Status Histological type AA GBM 9 45 Surgical Management type Biopsy 3 15 Partial excision 9 45 Near total excision

5 Temozolomide with Radiotherapy for the Treatment of... Response None of our patients achieved complete response (CR). There were 8 patients achieved partial response (40%). A similar number of patients {8 (40%)} had SD while 4 patients (20%) had progressive disease while on treatment. Table (2) lists the response rates Response No (n=20) % Partial response 8 40 The partial response was observed in 7 patients 40 years (35%) while it was observed in on patient only (5%) in patients > 40 years old group. None of the two female patients had PD. Seven patients with PR were males. Six patients has PS 0-1 had partial response. AA was the histological type in one out of 4 patients who had PD. None of the patients with biopsy only as a surgical procedure had PR while none of the patient with near total excision had PD. Table (3) lists the response rates by age, gender, performance status, histological type and type of surgery. Stable Disease 8 40 Progressive Disease 4 20 Table (3) Prognostic factor PR (n=8) SD (n= 8) PD (n= 4) No % No % No % Age (years) 40 (n= 14) > 40 (n= 6) Sex Male (n= 18) Female (n= 2) Performance Status 0-1 (n= 11) (n= 9) Histological type AA (n= 11) GBM (n= 9) Surgical Management type Biopsy (n= 3) Partial excision (n= 9) Near total excision (n= 8)

6 Ehab Abdou Toxicity Table (4) shows acute treatment morbidities. Hematological toxicity was mainly mild to moderate in severity. Six patients (30%) had grade I-II leucopenia. Seven patients (35%) had grade 1-2 anaemia while three patients (15%) had grade 1-2 thrombocytopenia. Nausea and vomiting were reported in all patients with grade 3-4 in half of them. Six patient (30%) developed grade 3-4 alopecia. Table (4): Acute treatment related toxicity Toxicity No % Haematological Grade I-II Leucopenia 6 30 Anaemia 7 35 Thrombocytopenia 3 15 Nausea and vomiting I-II III-IV Skin Reactions Grade I-II 6 30 Alopecia Grade I-II Grade III-IV 6 30 Survival At a median follow-up duration of 28 months (range, 12-56), median times to disease progression was 6.9 months and PFS rates was 30.6% at 12 months (Figure 1). Median survival was 12 months and OS rates was 65% at 12 months (Figure 2). DISCUSSION Anaplastic astrocytoma (AA) and glioblastoma multiform GBM are the most aggressive brain tumors in adults. Their clinical course is usually rapid and fatal, with a median survival of less than one year for GBM and 18 months for anaplastic astrocytoma. Despite surgery and RT with or without adjuvant chemotherapy, malignant glioma remains an almost uniformly fatal disease characterized by a rapid and devastating clinical course. 13 Cytoreduction surgical resection followed by radiotherapy concurrently with chemotherapy has been explored by using several agents with radio-sensitizing properties the most common chemotherapeutic agents, are, carmustine (BCNU), procarbazine/lomustine (CCNU), vincristine and temozolomide (TMZ). 14 Figure (1): Time to disease progression (months) 154

7 Temozolomide with Radiotherapy for the Treatment of... Figure (2): Overall survival. In treating patients with AA and GBM with adose of 60 Gy in single daily fractions of 1.8 to 2 Gy, five times per week. 25% of patients with GBM and 50% of those with AA exhibited a significant radiographic response by the completion of radiation therapy. Only 5% of patients had a complete tumor response, and a delayed response after irradiation was uncommon. 15 Results of our study were compared with other studies which used other chemotherapeutic agents as follow. In 1976 Wilson et al 16 used CCNU as single agent for malignant glioma in 36 patients the response (CR+PR+SD) was 44%. Another study involved modified regimen done by Levin et al., (1980) (17), the study included 46 patients, the response was 61%. In the current study we evaluate the antineoplastic efficacy and tolerability of temozolomide (temodal); which became at that time a new standard of treatment concurrently with radiotherapy for the AA and GMF postoperatively. Initially, the rational for combining temozolamide with radiotherapy is based on preclinical data suggesting additive or perhaps synergistic activity. In the present study, patients treated with adjuvant temozolomide plus radiotherapy.the overall response rate was 40% with possible improve in loco-reginal control in anaplastic astrocytoma AA and gliobastoma multiform GBM in comparison to other studies. In the study of A Capuya et al., 2001) (18), 18 patients were included with malignant glioma (15 GBM and 3 AA) treated with temozolomide (150 mg/m2 day for 5 days, repeated very 28 days for three cycles starting from the first day of radiotherapy. They reported an objective response of 44% and stable disease in 31.5% of patients which is comoarable to our results that came as 40%fro both the PR and SD.. Our results also were comparable to those obtained by Fatigante L et al., 2002, 10 study that included 89 patients with GBM treated with temozolomide 75mg/ m2/day one hour before radiotherapy, 7 days/week, after the end of radiotherapy started sequential treatment mg/m2/ day, for 5 days where objective response 50.5%, stable disease 26.9%. In the present study, the median time to disease progression for patients was 6.9 months. One year overall survival rate was 65% and median survival was 12 months. Stupp A. et al showed a comparable results 155

8 Ehab Abdou also when 45 patients were included for a similar protocol with a survival at one year equal to 67%. On the other hand, Brandes et al., (2000), 15 in their study on patients with newly diagnosed malignant glioma (73 patients with GBM and 20 patients with AA) reported an overall survival of 43% at one year. This discrepancy in results of these studies may be due to the difference in performance status and total number of patients among different studies. In our study there had been slightly increased toxicity rates specially grade III nausea and vomiting. Haematological toxicity were mild in both groups. None of patients were graded as III, IV. As regards non haematological morbidity, nausea and vomiting were the most common and occurred in 100% of patients Skin reactions as Grade 1-2 only were observed in 30% of patients. Alopecia wasobserved in all patients (100%). In Stupp, R et al.,2002) 20 trial of concomitant radiotherapy plus temozolomide therapy nonhematological toxicities were rare and mild to moderate in severity while grade 3 or 4 neutropenia, thrombocytopenia or both were observed only in 6% of patients. Conclusion Temozolomide and radiotherapy is a safe tolerable and effective treatment of newly diagnosed patients with AA and GBM. A better response rate was experienced in our experience in this trial that I scoming with the results obtained from many centers. Younger patients showed more tolerance and better response. Our center experience is coming with data supporting the efficacy of TMZ and its acceptable tolerance profile. REFERENCES 1. Galanis, E. and Buckner, J.: Chemotherapy for high-grade gliomas. Br J. Cancer (2000) 82: DeAngelis, LM.: Brain tmours. N. Eng. J. Med. (2001) 344: Radomized trial of Procarbazine, Lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: A medical Research Council trial. J. Clin. Oncol (2001) 19: Newlands, ES.; Stevens, MF.; Wedge, SR.: Temozolomide: A review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer treat. Rev. (1997) 23: Stupp, R.; Gander, M.; Leyvraz, S.; Current and future development in the use of temozolomide for the treatment of brain tumors. Lancet Oncol (2001) 2: Friedman, HS.; Kerby, T. and Calvert, H.; Temozolomide and treatment of malignant glioma. Clin. Cancer Res. (2000) 6: Yung, WK.; Albright, RE.; Olson J.; et al.: A phase II study of temozolomide vs. Procarbazine in patients with gliobastoma multiforme at first relapse. Br. J. Cancer (2000) 83: Yung, WK.; 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 (1999) Stupp, R.; Ostermann, S.; Leyvraz, S.; Cerebrospinal fluid levels of temozolomide as a surrogate marker for brain penetration. Proc. Am. Soc. Clin. Oncol. (2001) 20:59a (abstr 232). 10. Fatigante L.; Nocita AM.; Colantuoni OA.; Parenti G.: First line treatment in Gliobastoma multiforme: A multicenter phase II trial with temozolomide concomitant and sequential to radiotherapy. (EANO) V Congress, 7, Abstract no (2002) 124, Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) 1995 Mar 30; 31(5): Saunders DB and Trapp GR,et al :Basic and clinical biostatistics, 3nd edition, Connecticut, Appleton & Lang Hirose, Y.; Berger, MS.; Pieper, RO.: P53 Effects both the duration of G2/M arrest and the fate of temozolomide treated human glioblastoma cells. Cancer Res. (2001) 61: Van Rijn, J.; Heimans, JJ.; Van den Berg, J.; Survival of human glioma cells treated with various combination of temozolomide and x-rays. Int. J. Radiat. Oncol. Biol. Phys. (2000) 47: Brandes, A.; Pasetto, L.; Vastolas F. and Monfardini, S.: Temozolomide in patients with High Grade Gliomas. Oncology Vol. 59, Part, (2000) P Wilson C.B.; Guitin, P.; Boldrey.: Single agent chemotherapy of brain tumors. A five-years review. Arch. Neurol. (1976) 33: Levin V.A.; Edwards M.S.; Wright, D.C.: Modifined procarbazine, CCNU, and vincristine (PVC3) combination chemotherapy in the treatment of malignant brain tumours. Cancer Treaty Rep.; (1980) 46: Capuya et al. : Concomitant radiation therapy and temozolomide (TMZ) in the treatment of glioblastoma multiforme and Anaplastic astrocytoma: A pilot. 11th annual European concerence on cancer (ECCO)/Libson, Portugal. Abstract (2001) 1283, October Stupp R.; Ostermann S.; Dietrich, P.Y. Mirimanoff, R.O.: Daily Temozolomide (TMZ) and Concomitant Radiation followed by adjuvant TMZ for Newly diagnosed gliobastoma multiforme (GBM) Neuro-Oncology (5th Ann. Mtg. (2000) P. 296, Nov. 9-12). 20. Stupp R.; Ost ermann S.; Dietrich P.Y.; Mirimanoff R.O.: Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J. Clin. Oncol., (2002) Vol., 20 No. SP