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Reirradiation and lomustine in patients with relapsed high-grade gliomas
Int. J. Radiation Oncology Biol. Phys., Vol. 43, No. 4, pp. 789 –793, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter
PII S0360-3016(98)00457-X
CLINICAL INVESTIGATION
Brain
REIRRADIATION AND LOMUSTINE IN PATIENTS WITH RELAPSED HIGHGRADE GLIOMAS MAURO ARCICASA, M.D.,* MARIO RONCADIN, M.D.,* ETTORE BIDOLI, M.SC.,† ANATOLYI DEDKOV, M.D.,* MARCO GIGANTE, M.D.,* AND MAURO G.TROVO` , M.D.* *Divisione Oncologia Radioterapica and †Servizio Epidemiologia, Centro di Riferimento Oncologico, Aviano, Italy Purpose: The aim of this study was to evaluate the toxicity, response, and survival of patients with relapsed high-grade gliomas after radiation therapy (RT) combined with lomustine (CCNU). Methods and Materials: Thirty-one patients with relapsed gliomas at least 6 months after completion of RT were reirradiated. Twenty-four patients had a pathological diagnosis of high-grade gliomas, whereas 7 had a radiological diagnosis of relapsed malignant gliomas. The study focused on patients with high-grade relapsed gliomas. A total dose of 34.5 Gy was delivered in 23 fractions over 4.5 weeks. Oral administration of CCNU (130 mg/m2) was begun at the same time as RT, and was repeated every 6 weeks until disease progression, or up to 12 courses. Results: Twelve of 24 patients had surgery before RT plus CCNU treatment. Median interval between RT courses was 14 months (range 6 –73). All patients received a complete course of RT, and 22 of 24 patients received at least one course of CCNU. Objective responses were seen in 14 evaluable patients: 3 with partial response, 5 with stable disease, and 6 with progressive disease. Duration of partial response was 20, 9, and 8 months. Median time to progression and overall survival from the onset of retreatment were 8.4 months (range 1–22) and 13.7 months (range 1– 631), respectively. One case of G4 thrombocytopenia was observed. Five patients had G1 or G2 leucopenia and 3 patients had G3 leucopenia. Moderate nausea and vomiting were reported in 4 patients. One patient, after one course of CCNU, refused further chemotherapy. No significant difference in survival from relapse was found between patients who underwent surgery before RT plus CCNU and those who received only RT plus CCNU (p 5 0.74). Conclusion: Overall, the acute toxicity was moderate, and patient compliance was good. Reirradiation of high-grade glioma was associated with modest subjective and objective response rates. It is remarkable that median overall survival from relapse was 13.7 months. © 1999 Elsevier Science Inc. Gliomas, Radiotherapy, Surgery, Chemotherapy, Reirradiation.
INTRODUCTION
dose data (8, 9), a radiochemotherapy protocol for relapsed high-grade gliomas was defined. Survival benefit, tolerability, safety of the treatment, and feasibility in an outpatient setting were considered important clinical endpoints. The aim of the present study was to evaluate toxicity and response to radiotherapy (RT) and lomustine to treat relapsed high-grade gliomas. The patients enrolled in the protocol were referred by the colleagues of the “Progetto Ulisse” multidisciplinary study group (Appendix 1).
Each year, approximately 31,000 new primary brain tumors are diagnosed in the European population (1). Malignant gliomas account for 2.7% of the annual deaths from cancer. On average, 40 new patients with malignant gliomas are referred yearly to the Division of Radiotherapy at Centro di Riferimento Oncologico, Aviano, Italy. Despite macroscopically radical surgery or combined modality treatment, longterm survival of high-grade glioma is very rarely achieved (2, 3). Multifocal presentation of disease accounts for 5% of malignant gliomas, and distant spread of disease is rare. Conversely, local relapse is very frequent (4). Due to the natural history of disease, retreatment of patients who are relatively young and still in discrete general condition is often required; however, a standard retreatment protocol is not available. Given the proven superiority of combined treatments of malignant gliomas versus single agent treatment in terms of survival (3, 5–7) and previous brain tolerance
PATIENTS AND METHODS Patients From February 1988 to June 1997, 31 consecutive patients were enrolled in the protocol at the Division of Radiotherapy, General Hospital “S. Maria degli Angeli”, Pordenone, Italy, and at Centro di Riferimento Oncologico (CRO), Aviano, Pordenone. Eligibility criteria was patho-
Reprint requests to: Mauro Arcicasa, M.D., Divisione Oncologia Radioterapica, Centro di Riferimento Oncologico, via Pedemontana
Occidentale 12, 33081 Aviano (PN), Italy. E-mail: [email protected] Accepted for publication 21 October 1998. 789
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logical diagnosis of grade III or IV glioma relapsed at least 6 months after completion of RT (10, 11).
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Table 1. Characteristics of 24 patients with relapsed high-grade gliomas Characteristic
Treatment Treatment to the brain tumor was given in 1.5 Gy fractions, once a day, 5 days a week, to a dose of 34.5 Gy in 4.5 weeks. External beam RT was delivered by a 6 MV linear accelerator. Whole-brain RT was administered to 6 patients through 2 lateral parallel opposed fields. Hemi-brain RT was administered to 13 patients through 2 antero-posterior parallel opposed fields. Limited field irradiation was performed by rotational therapy technique, or 3-oblique-fields technique in 4 and 8 patients, respectively. Treatment volume was defined as the 2-cm margin of tissue surrounding the perimeter of the contrast enhancing lesion and edema on CT scans or MRI studies. Oral administration of lomustine (130 mg/m2) was begun with RT, and repeated every 6 weeks until progression, or up to 12 courses. A blood exam was performed before each course of lomustine. G1 or greater hematological toxicity implied a delay of the treatment of at least 1 week of further chemotherapy. Eight milligrams of corticosteroids were usually administered to patients during, and shortly after, the RT course, to prevent endocranial hypertension and related symptoms such as headache. Most patients required the administration of an antiemetic drug together with, and shortly after, lomustine. Evaluation of objective response according to WHO criteria was performed after 2 or 3 courses of chemotherapy by CT scan or MRI (9, 12). Follow-up was performed every 3 months. A worsening of each type of acute toxicity in each patient, according to WHO (13), was recorded. Karnofsky performance status (KPS) and neurological class (NC) (14) were recorded at follow-up. Comparisons of KPS and NC before treatment versus best evaluation after treatment were performed. Time to progression, survival from reirradiation, and overall survival from first diagnosis of glioma were reported for all patients. The actuarial survival curves were calculated by means of the Kaplan-Meier method, and differences were evaluated by log-rank test (15). A multivariate analysis by means of multiple regression applied to the Cox proportional model was used to estimate hazard ratios (HR) of death and corresponding 95% confidence intervals (CI 95%) after adjustment of the effect of age, histology, and time elapsed between first diagnosis and recurrence of high-grade gliomas (16). Local relapse after first RT course was observed in almost all of the patients, and repeat irradiation overlapped with previous volume irradiated; hence, cumulative radiation dose on the tumoral bed was calculated by the sum of the first radiation course total dose and reirradiation total dose. The latter was normalized at the conventional regimen by linear quadratic equation (17) and an a/b ratio of 3 (for late-reacting tissue).
Sex Age, yrs. Performance status Neurological class Histology Treatments before relapse
No. Male/Female 13/11 Median (range) 44 (23–73) Median (range) 70 (40–90) I/II/III 8/12/4 High-grade primitive glioma 18 High-grade relapsed glioma* 6 RT RT 1 CT Surgery 1 RT Surgery 1 RT 1 CT
Surgery after relapse Radical/Palliative Time between courses of radiotherapy Median (mos.) (range)
1 2 16 5 12 4/8 14 (5–73)
*Low-grade glioma was the first diagnosis. After relapse, the diagnosis was high-grade glioma. RT 5 radiotherapy; CT 5 chemotherapy.
RESULTS Twenty-four enrolled patients had a pathological diagnosis of high-grade relapsed glioma. Their characteristics at study entrance are reported in Table 1. After radiological diagnosis of brain tumors, all patients underwent either surgery or biopsy, followed by RT (21 of 24 patients received 60 Gy/30 fractions over 6 weeks; 3 patients received a total dose of 49, 50, and 56 Gy, respectively). Five patients received several courses of chemotherapy including vincristine, carmustine, and cis-platinum, and 2 patients received courses including vincristine, lomustine, and procarbazine. Another 7 patients with radiological diagnosis of relapsed glioma were treated according to the protocol. This report will focus on the 24 eligible patients, and data from the additional 7 patients will be presented separately. Feasibility and toxicity Median elapsed time between the first and second course of RT was 14 months (range 6 –72). Median total dose on the primitive glioma received by the patients with the first course was 60 Gy (range 46 – 60). All patients received a complete course of RT. Median cumulative radiation dose on the tumoral bed, at conventional fractionation, was 91 Gy (range 76 –92). Ten patients underwent reirradiation in an outpatient setting, while 14 patients were admitted to the hospital or CRO. The median number of chemotherapy courses administered to the patients was 3 (range 1–12). Subjective response of patients based on KPS and NC scales are reported in Table 2. Nonhematological acute toxicity consisted of local alopecia in almost all patients, and mild to moderate nausea and vomiting after lomustine in 4 patients. Hematological toxicity prevented further chemotherapy in 1 patient who had G4 thrombocytopenia. Administration of lomustine was delayed in 9 patients because of G1, G2, and G3 leucopenia in 4, 2, and 3 patients, respectively. Median
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Table 2. Subjective response to treatment Subjective response
PS
%
NC
%
No. of patients evaluated Improved PS or NC Stable Worsened
24 4 15 5
100 17 62 21
24 1 20 3
100 4 83 13
PS 5 Karnofsky performance status; NC 5 neurological class.
delay was 14 days (range 7–28). One patient refused to receive the second course of lomustine because of nausea and vomiting experienced after the first course. Response and survival Subjective response of 24 assessable patients is reported in Table 2. Ten patients were not evaluated for objective response for the following reasons: lack of parameter of disease radiologically evaluable after radical or cytoreductive surgery (8 patients) and early death after treatment (2 patients). Responses of 14 patients were: 3 partial response (PR) (21%), 5 stable disease (SD) (36%), and 6 progressive disease (PD) (43%). Duration of PRs were 8, 9, and 20 months, and duration of SDSs were 5, 7, 9, 91, and 151 months, respectively. Survival from relapse probability curve is reported in Fig. 1. Median time to progression was 8.4 months (CI 95%: 4.7–10.8) and the range was 1–22 months. Median survival from relapse was 13.7 months (CI 95%: 9.8 –17.5) and the range was 1– 631 (Fig. 1). Median overall survival from first diagnosis of glioma was 45.4 months (CI 95%: 24 – 60.9) and the range was 13–93 months. At the end of 1997, 3 of 24 patients were alive, with progressive disease (191, 621, and 631 months of survival from relapse, respectively). Twelve of 24 patients had surgery on the relapsed glioma before RT and lomustine. No significative difference of survival after relapse was found between patients who received surgical treatment before radiochemotherapy (Fig. 2). Estimated hazard ratio (HR) of death did not show any significant difference between pa-
Fig. 1. Overall survival from relapse of high-grade gliomas.
Fig. 2. Overall survival from relapse of high-grade gliomas for patients who underwent surgery after relapse ( ——— ) and those who did not (---------).
tients who received surgical treatment (HR 5 0.83, CI 95%: 0.22–3.14) or not (HR 5 1) before radiochemotherapy. Seven patients with radiological diagnosis of relapsed glioma received RT and lomustine according to the protocol. Their characteristics and response to treatment are summarized as follows: median age 51 years (range 30 –77); baseline KPS 70 (range 40 –90); courses of lomustine 4 (range 0 – 8); objective response: 5 SD, 1 PD, and 1 patient not evaluated; subjective response: PS – 3 stable, and 4 worsened, CN – 1 improved, 2 stable, and 4 worsened; time to progression 7 months (range 5–14); survival from retreatment 7 months (range 5–16); and overall survival 26 months (range 14 – 69). DISCUSSION Reirradiation modality of brain tumors is a controversial issue (18). Reirradiation on the same target volume with fractionated external beam RT is rarely performed, due to concerns regarding cumulative toxicity (19). The main factors determining tolerance of the brain to irradiation appear to be total dose, volume of brain irradiated, fraction size, use of chemotherapy, and age of the patient (9, 18). The radiation dose associated with a necrosis probability of 5% (TD5) has been estimated to lie between 45 and 60 Gy for conventional fractionated irradiation to whole- or partialbrain volumes (7, 8, 19). Recent evidence suggests that there may be some recovery of radiation tolerance within the central nervous system. Van der Kogel reported on the incidence of myelopathy in rats retreated at variable intervals after a course of cervical spine irradiation (20). In general, the tolerance to retreatment increased with increasing interval to retreatment, and decreasing initial radiation dose. No similar data are available for repeat brain irradiation in humans, although a “remembered dose” of about 50% of the original radiation dose after 1–2 years has been suggested (8, 21). In the present protocol, cumulative radiation dose did not exceed 90 Gy, as previously suggested (18). Adding a “remembered dose” of 30 Gy and the total
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reirradiation dose normalized at conventional regimen (31 Gy), the weighted cumulative dose was roughly 61 Gy. Individualized repeat radiation doses should be determined in future protocols depending on the time elapsed from the first radiation therapy course and the irradiated volumes overlap. Higher safe repeat doses could be delivered in selected patients; however, guidelines in implementing these variables in treatment planning are required. The treatment was feasible in an outpatient setting, and the acute toxicity was acceptable. In some cases, it was difficult to separate toxicity due to retreatment versus tumor progression. Within the limits due to patient numbers and follow-up length, our report shows that retreatment of patients with relapsed high-grade gliomas was safe. Observed subjective response could be partially due to corticosteroids administered daily during and after RT. In most patients, the daily dose was reduced after completion of RT, but was not stopped. Interestingly, median overall survival of patients with grade III and IV glioma appeared higher than that previously reported in the literature (22). It is likely that the 6-month eligibility requirement may account for, at least partially, the encouraging survival rates. Nevertheless, the objective response rate, the duration of response, and disease stabilization documents that this treatment has some effectiveness on relapsed high-grade gliomas. Whether the apparently prolonged survival is ascribable either to the second-line treatment or to eligibility
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criteria, resulting in a positive selection of the patients, is an issue that cannot be addressed with the present study. A large retrospective study (23) of brain tumors reported that benefits from RT of high-grade gliomas, measured as survival, appear to be modest, but greater than any chemotherapy tested thus far. Nevertheless, a meta-analysis comparing radiochemotherapy versus RT for malignant gliomas reported that adjuvant chemotherapy is advantageous and should be considered part of the standard therapeutic regimen (5). It was previously reported that reoperation of relapsed gliomas in selected patients (24, 25) was significant in terms of survival; however, in reviewing survival data of the present study, it was not obvious that surgery on relapsed high-grade gliomas results in prolonged survival or freedom from disease. Age, KPS, histology, and time to relapse after first RT course in the patients of the two groups were retrospectively compared, and a positive selection of the surgical group was found (data not shown). A comparison was made between patients who underwent surgery of relapsed gliomas before RT plus lomustine, and patients who received only RT plus lomustine. The log-rank test and Cox proportional model did not find significant differences of time to progression and overall survival between the two groups. Within the limits of the small number of patients in a nonrandomized study, surgery of relapsed gliomas before radiochemotherapy appears to be an overtreatment.
REFERENCES 1. Jensen OM, Este´ve J, Møller H, et al. Cancer in European community and its member states. Eur J Cancer 1990;26: 1167–1256. 2. Curran WJ, Scott CB, Horton J, et al. Recursive partitioning analysis in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85:704 –710. 3. Leibel SA, Scott CB, Loeffler JS. Contemporary approaches to treatment of malignant gliomas with radiation therapy. Semin Oncol 1994;21:198 –219. 4. Wallner KE, Galicich JH, Krol G, et al. Pattern of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int Radiat Oncol Biol Phys 1989;16:1405–1409. 5. Fine HA, Dear KBG, Loeffler JS, et al. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993;71:2585–2597. 6. Levin VA, Silver P, Hannigan J, et al. Superiority of postradiotherapy adjuvant chemotherapy with CCNU, procarbazine and vincristine (PCV) over BCNU in anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 1990; 18:321–329. 7. Shapiro WR, Green SB, Burger PC. Randomized trial of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. J Neurosurg 1989;71:1–9. 8. Enami B, Lyman J, Brown A. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991; 21:109 –122. 9. Schultheiss TE, Kun LE, Ang KK, et al. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 1995; 31:1093–1112. 10. Bruner JM. Neuropathology of malignant gliomas. Semin Oncol 1994;21:126 –138.
11. Burger PC, Vogel FS, Green SB, et al. Glioblastoma multiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer 1985;56:1106 –1111. 12. Levin VA, Leibel SA, Gutin PH. Neoplasms of central nervous system. In: De Vita TV, Hellman S, Rosemberg SA, editors. Cancer: principles and practice of oncology. Philadelphia, New York: Lippincott-Raven; 1997. p. 2049. 13. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981;47:207–214. 14. Order SE, Hellman S, von Essen C, et al. Movement in quality of survival following whole-brain irradiation for brain metastases. Radiology 1968;91:149 –153. 15. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Statist Soc 1958;53:457– 481. 16. Cox DR. Regression models and life tables. J Roy Statist Soc 1972;34(Series B):187–220. 17. Lee SP, Leu MY, Smathers JB, et al. Biologically effective dose distribution based on the linear quadratic model and its clinical relevance. Int J Radiat Oncol Biol Phys 1995;33:375–389. 18. Bauman GS, Sneed PK, Wara WM, et al. Reirradiation of primary CNS tumors. Int J Radiat Oncol Biol Phys 1996; 36:433– 441. 19. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys 1980;6:1215–1228. 20. Van der Kogel AJ. Clinical implications of radiological studies on CNS tolerance. In: Karim L, editor. Glioma. Berlin: Springer Verlag; 1991. p. 179 –187. 21. Flickinger JC, Deutsch M, Lunsford LD. Repeat megavoltage irradiationof pituitary and suprasellar tumors. Int J Radiat Oncol Biol Phys 1989; 17:171–175. 22. Wara MW, Bauman GS, Sneed PK, et al. Brain, brain stem, and cerebellum. In: Perez CA, Brady LW, editors. Principles
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and practice of radiation oncology. Philadelphia, New York: Lippincott-Raven; 1998. p. 800 – 801. 23. Blomgren H. Brain tumors. Acta Oncol 1996;35:16 –21. 24. Berger MS, Tucker A, Spence A, et al. Reoperation for glioma. Clin Neurosurg 1992;39:172–186.
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25. Simpson JR, Horton J, Scott C, et al. Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: Results of three consecutive RTOG clinical trials. Int J Radiat Oncol Biol Phys 1993; 26:239 –244.
APPENDIX 1 “Progetto Ulisse” members who contributed to the study: Dr. L. Antonutti, Dr. F. Chiodi Grandi Dr. G. Grandi Dr. M. Skrap, Dr. A. Melatini Dr. R. Danielis Dr. P. P. Janes, Dr. G. Vindigni Dr. R. Panizzo Dr. A. Rinaldi Prof. G. Cartei, Dr. L. Clocchiatti, Dr. E. Vigevani Dr. G. Fabris, Dr. A. Lavaroni Dr. E. Covezzi, Dr. G. Tortorici
Neurologia Anatomia Patologica Neurochirurgia Neurologia Neurochirurgia Anatomia Patologica Neurologia Oncologia Medica Neuroradiologia Neurologia
Trieste Trieste Trieste Gorizia Udine Udine Udine Udine Udine Pordenone
PII S0360-3016(98)00457-X
CLINICAL INVESTIGATION
Brain
REIRRADIATION AND LOMUSTINE IN PATIENTS WITH RELAPSED HIGHGRADE GLIOMAS MAURO ARCICASA, M.D.,* MARIO RONCADIN, M.D.,* ETTORE BIDOLI, M.SC.,† ANATOLYI DEDKOV, M.D.,* MARCO GIGANTE, M.D.,* AND MAURO G.TROVO` , M.D.* *Divisione Oncologia Radioterapica and †Servizio Epidemiologia, Centro di Riferimento Oncologico, Aviano, Italy Purpose: The aim of this study was to evaluate the toxicity, response, and survival of patients with relapsed high-grade gliomas after radiation therapy (RT) combined with lomustine (CCNU). Methods and Materials: Thirty-one patients with relapsed gliomas at least 6 months after completion of RT were reirradiated. Twenty-four patients had a pathological diagnosis of high-grade gliomas, whereas 7 had a radiological diagnosis of relapsed malignant gliomas. The study focused on patients with high-grade relapsed gliomas. A total dose of 34.5 Gy was delivered in 23 fractions over 4.5 weeks. Oral administration of CCNU (130 mg/m2) was begun at the same time as RT, and was repeated every 6 weeks until disease progression, or up to 12 courses. Results: Twelve of 24 patients had surgery before RT plus CCNU treatment. Median interval between RT courses was 14 months (range 6 –73). All patients received a complete course of RT, and 22 of 24 patients received at least one course of CCNU. Objective responses were seen in 14 evaluable patients: 3 with partial response, 5 with stable disease, and 6 with progressive disease. Duration of partial response was 20, 9, and 8 months. Median time to progression and overall survival from the onset of retreatment were 8.4 months (range 1–22) and 13.7 months (range 1– 631), respectively. One case of G4 thrombocytopenia was observed. Five patients had G1 or G2 leucopenia and 3 patients had G3 leucopenia. Moderate nausea and vomiting were reported in 4 patients. One patient, after one course of CCNU, refused further chemotherapy. No significant difference in survival from relapse was found between patients who underwent surgery before RT plus CCNU and those who received only RT plus CCNU (p 5 0.74). Conclusion: Overall, the acute toxicity was moderate, and patient compliance was good. Reirradiation of high-grade glioma was associated with modest subjective and objective response rates. It is remarkable that median overall survival from relapse was 13.7 months. © 1999 Elsevier Science Inc. Gliomas, Radiotherapy, Surgery, Chemotherapy, Reirradiation.
INTRODUCTION
dose data (8, 9), a radiochemotherapy protocol for relapsed high-grade gliomas was defined. Survival benefit, tolerability, safety of the treatment, and feasibility in an outpatient setting were considered important clinical endpoints. The aim of the present study was to evaluate toxicity and response to radiotherapy (RT) and lomustine to treat relapsed high-grade gliomas. The patients enrolled in the protocol were referred by the colleagues of the “Progetto Ulisse” multidisciplinary study group (Appendix 1).
Each year, approximately 31,000 new primary brain tumors are diagnosed in the European population (1). Malignant gliomas account for 2.7% of the annual deaths from cancer. On average, 40 new patients with malignant gliomas are referred yearly to the Division of Radiotherapy at Centro di Riferimento Oncologico, Aviano, Italy. Despite macroscopically radical surgery or combined modality treatment, longterm survival of high-grade glioma is very rarely achieved (2, 3). Multifocal presentation of disease accounts for 5% of malignant gliomas, and distant spread of disease is rare. Conversely, local relapse is very frequent (4). Due to the natural history of disease, retreatment of patients who are relatively young and still in discrete general condition is often required; however, a standard retreatment protocol is not available. Given the proven superiority of combined treatments of malignant gliomas versus single agent treatment in terms of survival (3, 5–7) and previous brain tolerance
PATIENTS AND METHODS Patients From February 1988 to June 1997, 31 consecutive patients were enrolled in the protocol at the Division of Radiotherapy, General Hospital “S. Maria degli Angeli”, Pordenone, Italy, and at Centro di Riferimento Oncologico (CRO), Aviano, Pordenone. Eligibility criteria was patho-
Reprint requests to: Mauro Arcicasa, M.D., Divisione Oncologia Radioterapica, Centro di Riferimento Oncologico, via Pedemontana
Occidentale 12, 33081 Aviano (PN), Italy. E-mail: [email protected] Accepted for publication 21 October 1998. 789
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Physics
logical diagnosis of grade III or IV glioma relapsed at least 6 months after completion of RT (10, 11).
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Table 1. Characteristics of 24 patients with relapsed high-grade gliomas Characteristic
Treatment Treatment to the brain tumor was given in 1.5 Gy fractions, once a day, 5 days a week, to a dose of 34.5 Gy in 4.5 weeks. External beam RT was delivered by a 6 MV linear accelerator. Whole-brain RT was administered to 6 patients through 2 lateral parallel opposed fields. Hemi-brain RT was administered to 13 patients through 2 antero-posterior parallel opposed fields. Limited field irradiation was performed by rotational therapy technique, or 3-oblique-fields technique in 4 and 8 patients, respectively. Treatment volume was defined as the 2-cm margin of tissue surrounding the perimeter of the contrast enhancing lesion and edema on CT scans or MRI studies. Oral administration of lomustine (130 mg/m2) was begun with RT, and repeated every 6 weeks until progression, or up to 12 courses. A blood exam was performed before each course of lomustine. G1 or greater hematological toxicity implied a delay of the treatment of at least 1 week of further chemotherapy. Eight milligrams of corticosteroids were usually administered to patients during, and shortly after, the RT course, to prevent endocranial hypertension and related symptoms such as headache. Most patients required the administration of an antiemetic drug together with, and shortly after, lomustine. Evaluation of objective response according to WHO criteria was performed after 2 or 3 courses of chemotherapy by CT scan or MRI (9, 12). Follow-up was performed every 3 months. A worsening of each type of acute toxicity in each patient, according to WHO (13), was recorded. Karnofsky performance status (KPS) and neurological class (NC) (14) were recorded at follow-up. Comparisons of KPS and NC before treatment versus best evaluation after treatment were performed. Time to progression, survival from reirradiation, and overall survival from first diagnosis of glioma were reported for all patients. The actuarial survival curves were calculated by means of the Kaplan-Meier method, and differences were evaluated by log-rank test (15). A multivariate analysis by means of multiple regression applied to the Cox proportional model was used to estimate hazard ratios (HR) of death and corresponding 95% confidence intervals (CI 95%) after adjustment of the effect of age, histology, and time elapsed between first diagnosis and recurrence of high-grade gliomas (16). Local relapse after first RT course was observed in almost all of the patients, and repeat irradiation overlapped with previous volume irradiated; hence, cumulative radiation dose on the tumoral bed was calculated by the sum of the first radiation course total dose and reirradiation total dose. The latter was normalized at the conventional regimen by linear quadratic equation (17) and an a/b ratio of 3 (for late-reacting tissue).
Sex Age, yrs. Performance status Neurological class Histology Treatments before relapse
No. Male/Female 13/11 Median (range) 44 (23–73) Median (range) 70 (40–90) I/II/III 8/12/4 High-grade primitive glioma 18 High-grade relapsed glioma* 6 RT RT 1 CT Surgery 1 RT Surgery 1 RT 1 CT
Surgery after relapse Radical/Palliative Time between courses of radiotherapy Median (mos.) (range)
1 2 16 5 12 4/8 14 (5–73)
*Low-grade glioma was the first diagnosis. After relapse, the diagnosis was high-grade glioma. RT 5 radiotherapy; CT 5 chemotherapy.
RESULTS Twenty-four enrolled patients had a pathological diagnosis of high-grade relapsed glioma. Their characteristics at study entrance are reported in Table 1. After radiological diagnosis of brain tumors, all patients underwent either surgery or biopsy, followed by RT (21 of 24 patients received 60 Gy/30 fractions over 6 weeks; 3 patients received a total dose of 49, 50, and 56 Gy, respectively). Five patients received several courses of chemotherapy including vincristine, carmustine, and cis-platinum, and 2 patients received courses including vincristine, lomustine, and procarbazine. Another 7 patients with radiological diagnosis of relapsed glioma were treated according to the protocol. This report will focus on the 24 eligible patients, and data from the additional 7 patients will be presented separately. Feasibility and toxicity Median elapsed time between the first and second course of RT was 14 months (range 6 –72). Median total dose on the primitive glioma received by the patients with the first course was 60 Gy (range 46 – 60). All patients received a complete course of RT. Median cumulative radiation dose on the tumoral bed, at conventional fractionation, was 91 Gy (range 76 –92). Ten patients underwent reirradiation in an outpatient setting, while 14 patients were admitted to the hospital or CRO. The median number of chemotherapy courses administered to the patients was 3 (range 1–12). Subjective response of patients based on KPS and NC scales are reported in Table 2. Nonhematological acute toxicity consisted of local alopecia in almost all patients, and mild to moderate nausea and vomiting after lomustine in 4 patients. Hematological toxicity prevented further chemotherapy in 1 patient who had G4 thrombocytopenia. Administration of lomustine was delayed in 9 patients because of G1, G2, and G3 leucopenia in 4, 2, and 3 patients, respectively. Median
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Table 2. Subjective response to treatment Subjective response
PS
%
NC
%
No. of patients evaluated Improved PS or NC Stable Worsened
24 4 15 5
100 17 62 21
24 1 20 3
100 4 83 13
PS 5 Karnofsky performance status; NC 5 neurological class.
delay was 14 days (range 7–28). One patient refused to receive the second course of lomustine because of nausea and vomiting experienced after the first course. Response and survival Subjective response of 24 assessable patients is reported in Table 2. Ten patients were not evaluated for objective response for the following reasons: lack of parameter of disease radiologically evaluable after radical or cytoreductive surgery (8 patients) and early death after treatment (2 patients). Responses of 14 patients were: 3 partial response (PR) (21%), 5 stable disease (SD) (36%), and 6 progressive disease (PD) (43%). Duration of PRs were 8, 9, and 20 months, and duration of SDSs were 5, 7, 9, 91, and 151 months, respectively. Survival from relapse probability curve is reported in Fig. 1. Median time to progression was 8.4 months (CI 95%: 4.7–10.8) and the range was 1–22 months. Median survival from relapse was 13.7 months (CI 95%: 9.8 –17.5) and the range was 1– 631 (Fig. 1). Median overall survival from first diagnosis of glioma was 45.4 months (CI 95%: 24 – 60.9) and the range was 13–93 months. At the end of 1997, 3 of 24 patients were alive, with progressive disease (191, 621, and 631 months of survival from relapse, respectively). Twelve of 24 patients had surgery on the relapsed glioma before RT and lomustine. No significative difference of survival after relapse was found between patients who received surgical treatment before radiochemotherapy (Fig. 2). Estimated hazard ratio (HR) of death did not show any significant difference between pa-
Fig. 1. Overall survival from relapse of high-grade gliomas.
Fig. 2. Overall survival from relapse of high-grade gliomas for patients who underwent surgery after relapse ( ——— ) and those who did not (---------).
tients who received surgical treatment (HR 5 0.83, CI 95%: 0.22–3.14) or not (HR 5 1) before radiochemotherapy. Seven patients with radiological diagnosis of relapsed glioma received RT and lomustine according to the protocol. Their characteristics and response to treatment are summarized as follows: median age 51 years (range 30 –77); baseline KPS 70 (range 40 –90); courses of lomustine 4 (range 0 – 8); objective response: 5 SD, 1 PD, and 1 patient not evaluated; subjective response: PS – 3 stable, and 4 worsened, CN – 1 improved, 2 stable, and 4 worsened; time to progression 7 months (range 5–14); survival from retreatment 7 months (range 5–16); and overall survival 26 months (range 14 – 69). DISCUSSION Reirradiation modality of brain tumors is a controversial issue (18). Reirradiation on the same target volume with fractionated external beam RT is rarely performed, due to concerns regarding cumulative toxicity (19). The main factors determining tolerance of the brain to irradiation appear to be total dose, volume of brain irradiated, fraction size, use of chemotherapy, and age of the patient (9, 18). The radiation dose associated with a necrosis probability of 5% (TD5) has been estimated to lie between 45 and 60 Gy for conventional fractionated irradiation to whole- or partialbrain volumes (7, 8, 19). Recent evidence suggests that there may be some recovery of radiation tolerance within the central nervous system. Van der Kogel reported on the incidence of myelopathy in rats retreated at variable intervals after a course of cervical spine irradiation (20). In general, the tolerance to retreatment increased with increasing interval to retreatment, and decreasing initial radiation dose. No similar data are available for repeat brain irradiation in humans, although a “remembered dose” of about 50% of the original radiation dose after 1–2 years has been suggested (8, 21). In the present protocol, cumulative radiation dose did not exceed 90 Gy, as previously suggested (18). Adding a “remembered dose” of 30 Gy and the total
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reirradiation dose normalized at conventional regimen (31 Gy), the weighted cumulative dose was roughly 61 Gy. Individualized repeat radiation doses should be determined in future protocols depending on the time elapsed from the first radiation therapy course and the irradiated volumes overlap. Higher safe repeat doses could be delivered in selected patients; however, guidelines in implementing these variables in treatment planning are required. The treatment was feasible in an outpatient setting, and the acute toxicity was acceptable. In some cases, it was difficult to separate toxicity due to retreatment versus tumor progression. Within the limits due to patient numbers and follow-up length, our report shows that retreatment of patients with relapsed high-grade gliomas was safe. Observed subjective response could be partially due to corticosteroids administered daily during and after RT. In most patients, the daily dose was reduced after completion of RT, but was not stopped. Interestingly, median overall survival of patients with grade III and IV glioma appeared higher than that previously reported in the literature (22). It is likely that the 6-month eligibility requirement may account for, at least partially, the encouraging survival rates. Nevertheless, the objective response rate, the duration of response, and disease stabilization documents that this treatment has some effectiveness on relapsed high-grade gliomas. Whether the apparently prolonged survival is ascribable either to the second-line treatment or to eligibility
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criteria, resulting in a positive selection of the patients, is an issue that cannot be addressed with the present study. A large retrospective study (23) of brain tumors reported that benefits from RT of high-grade gliomas, measured as survival, appear to be modest, but greater than any chemotherapy tested thus far. Nevertheless, a meta-analysis comparing radiochemotherapy versus RT for malignant gliomas reported that adjuvant chemotherapy is advantageous and should be considered part of the standard therapeutic regimen (5). It was previously reported that reoperation of relapsed gliomas in selected patients (24, 25) was significant in terms of survival; however, in reviewing survival data of the present study, it was not obvious that surgery on relapsed high-grade gliomas results in prolonged survival or freedom from disease. Age, KPS, histology, and time to relapse after first RT course in the patients of the two groups were retrospectively compared, and a positive selection of the surgical group was found (data not shown). A comparison was made between patients who underwent surgery of relapsed gliomas before RT plus lomustine, and patients who received only RT plus lomustine. The log-rank test and Cox proportional model did not find significant differences of time to progression and overall survival between the two groups. Within the limits of the small number of patients in a nonrandomized study, surgery of relapsed gliomas before radiochemotherapy appears to be an overtreatment.
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APPENDIX 1 “Progetto Ulisse” members who contributed to the study: Dr. L. Antonutti, Dr. F. Chiodi Grandi Dr. G. Grandi Dr. M. Skrap, Dr. A. Melatini Dr. R. Danielis Dr. P. P. Janes, Dr. G. Vindigni Dr. R. Panizzo Dr. A. Rinaldi Prof. G. Cartei, Dr. L. Clocchiatti, Dr. E. Vigevani Dr. G. Fabris, Dr. A. Lavaroni Dr. E. Covezzi, Dr. G. Tortorici
Neurologia Anatomia Patologica Neurochirurgia Neurologia Neurochirurgia Anatomia Patologica Neurologia Oncologia Medica Neuroradiologia Neurologia
Trieste Trieste Trieste Gorizia Udine Udine Udine Udine Udine Pordenone