- Email: [email protected]
3D-recurrence-patterns of gliobastomas after CT-planned postoperative irradiation
Radiotherapy and Oncology 53 (1999) 53±57
Short communication
www.elsevier.com/locate/radonline
3D-recurrence-patterns of gliobastomas after CT-planned postoperative irradiation Ulrich Oppitz*, Dirk Maessen, Hildegard Zunterer, Susanne Richter, Michael Flentje Department of Radiation Oncology, University of WuÈrzburg, Josef-Schneider-Strasse 11, 97080 WuÈrzburg, Germany Received 13 August 1998; received in revised form 16 July 1999; accepted 23 July 1999
Abstract Background and purpose: The introduction of computed-tomography as an advanced planning tool for the irradiation of intracranial tumours led to a controversial discussions about the optimal target-volume for the primary and postoperative treatment of malignant gliomas. This study analyses the three-dimensional tumour regrowth pattern relative to the treated volume which included the macroscopic preoperative tumour and 2-cm safety margin. Materials and methods: Seventy-nine patients with histologically-con®rmed Glioblastoma multiforma and documented recurrence who were irradiated in our department between 1990 and 1996 were reviewed. With the help of a computer program written for this purpose, the PTV of the CT-based treatment plan was reconstructed and its spatial outline compared with the reconstructed volume of the recurrent tumour in the control CT-study. Results: In 33 out 34 patients for which the CT-study showing tumour-recurrence was available the recurrence was completely situated within the original 90%-isodose. Only one tumour surpassed the outside surface of the PTV but was predominantly situated within the original tumourbed and suggests a tumour-regrowth within the high dose volume. Conclusions: The above results show that target-volumes based on the preoperative size of the enhanced tumour mass well cover the site of recurrence in nearly all cases. The ®ndings suggest dose escalation to a more restricted volume. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Malignant gliomas; Radiotherapy; CT-Planning; Recurrence-pattern
1. Introduction The diagnosis of malignant glioma is usually associated with a poor prognosis. Median survival after surgical resection with no further treatment is about 14 weeks. Postoperative whole brain irradiation (WBI) increased the median survival to 35 weeks in prospectively controlled trials [21,13]. After the introduction of computed-tomography as a planning tool for the irradiation of intracranial tumours, many authors tried to de®ne the optimal treatment-volume for the primary and postoperative treatment of malignant gliomas. Contrary to earlier assumptions [18], Hochberg and Pruitt [9] reported in 1980, that 80% of glioblastomas recurred completely and 10% partially within the original tumoursite and that multicentricity was a rather uncommon phenomenon. Wallner et al. [23] superimposed anatomically corresponding CT images of the largest preoperative and recur* Corresponding author.
rent tumour areas and found that 78 % of the recurrences were localised within a 2.0-cm margin of the initial tumour bed. In contradiction to these ®ndings suggesting the introduction of localised brain irradiation as a standard treatment procedure, major studies by Kelly et al. [10], Burger et al. [2] and Halperin et al. [7] reported that atypical cells may surpass the perifocal edematous area, which is usually de®ned water by neuroradiologists. They came to the conclusion that a 2±3 cm safety-margin around the contrast-enhancing tumour-area will often underestimate the spread of the neoplasm. Halperin et al. [8] state that `only portals which encompassed the peritumoural edema and a 3 cm safety-margin around the edema adequately covered the histologically identi®ed tumour', the missed microscopic tumour in®ltrations may be the cause of treatment failure if the bulky area could be controlled. This led to considerable uncertainties concerning the optimal target volume in the postoperative treatment of glioblastoma multiforme (GBM). The margins of the planning target volume vary quite signi®cantly between different institutions. The safety zone around the preoperative contrast-
0167-8140/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0167-814 0(99)00117-6
54
U. Oppitz et al. / Radiotherapy and Oncology 53 (1999) 53±57
enhancing tumour ranged between 1±4 cm [1,5,11,23] up to the complete peritumoural edema 1 2±3 cm safety margin [20]. It is the aim of this study to analyse the localisation and 3D patterns of tumour recurrences after the introduction of a CT-based 3D-treatment planning concept and limited volume irradiation in the treatment of malignant gliomas.
ted volume limited to the preoperative contrast-enhancing tumour-area only. The patients were irradiated with 60Co and/or 5 MV-photons in a multiple-®eld-technique with single fractions ranging from 1.8 to 3.0 Gy (median, 2.0 Gy). The majority of the patients (74.6%) received one fraction a day, 25.4% were irradiated twice a day, ten times a week with single fractions of 1.8 Gy up to a total dose of 54 Gy.
2. Materials and methods Our treatment-strategy for GBM changed gradually from WBI to a localised 3D CT-planned irradiation in 1989. Records were reviewed from 79 patients with histological con®rmed Glioblastoma multiforme (WHO grade IV) and documented tumour recurrence who were irradiated in the Deptartment of Radiation Oncology, University of WuÈrzburg between 1990 and 1996. Six patients had to be excluded from further analysis because of following criteria of exclusion: age , 18 years, whole brain irradiation (WBI) only, total dose below 40 Gy and multilocular growth with more than one target-volume. The age at time of diagnosis ranged between 24 and 75 years, with a median age of 57 years. Forty three (59%) were under and 30 (41%) above 60 years of age. There were 30 female (41%) and 43 (59%) male patients. Thirty four of the tumours were situated in the right, 30 in the left and three in both hemispheres, six pretherapeutic CTstudies were not available. Twenty-four percent of the surgical procedures were biopsies only (of which 87% were stereotactic) and 76% were resections, 25% gross total excisions and 75% subtotal resections, in one patient the extent of surgery could not be determined. Four patients were lost from follow-up. In 34 patients complete CT information (preoperative CT, planning CT with 3D-dose-representation and CT and time of progression) was available for the 3D-recurrence pattern analyses. These patients formed the base of the study. No signi®cant differences for age at diagnosis, dosage, treatment technique, primary tumour-volume, follow-uptime and survival between the study group and the whole collective was detected. 2.1. Radiation therapy The postoperative radiation treatment included CT-based geometrical 3D-treatment planning of a target-volume which included the preoperative contrast-enhancing tumour-volume in every case. In most cases a cone down technique was used. The initial treated volume either enclosed the whole brain (WBI) with a boost irradiation to the gross tumour volume or included the preoperative contrast-enhancing macroscopic tumour-volume and a 2 cm safety margin. Depending on the size of the tumour it was either irradiated in this manner throughout the whole treatment or was followed by boost-irradiation with a trea-
2.2. Reconstruction of the volume encompassed by the 90%isodose (treated volume) The CT-based treatment plan was the starting point for de®nition of a co-ordinate-system for the spatial outline of the 90%-isodose. If the treatment was performed as a cone down in two series the 90% isodose of the boost series was used for this analysis. The volume encompassed by the 90%-isodose-surface was considered the treated volume. The origins of the x- and y-axis were de®ned by the isocentre of the plan. The 0-value of the z-axis was centred between the most cranial and caudal CT-scan of the irradiation volume. A polygon was ®tted to the outline of the 90%isodose in each CT-slice. For every point describing the polyeder the x-,y- and z-co-ordinate relative to the origin was measured. 2.3. Volume-reconstruction of the tumour-recurrence A new contrast-enhancing structure after complete extirpation or regrowth of residual tumour after partial resection with clinical or radiological con®rmation in further follow up were de®ned as tumour-recurrence. Positron emission tomographic (PET)-scanning which is helpful to differentiate between recurrent tumour and radiation necrosis [6] was not available at that time. For the reconstruction of the recurrent-tumour volume and projection into the former treatment-plan the co-ordinate system of the treatment-planning CT had to be transferred to the CT-scan demonstrating the recurrent tumour. For this purpose the z-axis had to be marked in the scout of the planning-CT. Afterwards the 0coordinate of the z-axis was transferred from this scout to the scout of the new CT using a subtrascope (Siemens, an instrument originally developed for superimposing diagnostic X-ray images, a precursor of digital subtraction angiography) under consideration of possible differences in head inclination between the two CT-examinations. This de®ned a horizontal central plane identical to the treatment set-up. Then the origin of the co-ordinate-system (isocentre of the treatment plan) was transferred to the new CT using relations to anatomical landmarks and projected to all CT-slices (vertical central plane) showing recurrent tumour. Now the recurrent-tumour-volume was reconstructed identical to the procedure described above for the volume encompassed by the 90%-isodose.
U. Oppitz et al. / Radiotherapy and Oncology 53 (1999) 53±57
55
Fig. 1. (a) Example of a recurrent tumour completely localised within the volume of the 90%-isodose from three different viewpoints. (b) Example of the recurrent tumour partially surpassing the volume of the 90%-isodose from three different viewpoints.
2.4. Relationship between 90%-isodose- surface and recurrent-tumour volume With the help of a computer program (based on Mathematica TM) written for this purpose the volume encompassed by the 90%-isodose and a 3D-reconstruction of the recurrent-tumour were calculated using the common origin of the co-ordinate systems and the angulation resulting from different head inclinations in the planning CT and the CTstudy showing recurrence. The surface of each polygon was calculated and multiplied by the thickness of the CT-slice for volume determination. Then both volumes were projected into each other using the co-ordinate system as described before. For both volumes the centres of gravity and its distance were calculated. The calculations were rechecked with the help of the graphical reconstructions of the tumour-recurrence and the treated volume from three different viewpoints (vp) (Fig. 1a,b). Finally the closest distance between the outmost border of the recurrent tumour and the 90%-isodose was determined.
3. Results 3.1. Patients treatment In 34 cases post-treatment CT-scans with recurrent tumour were available for analysis. Clinical deterioration was the reason for these CT's in all cases. The postoperative irradiation of the patients was not homogeneous. Seven
patients received a cone-down boost to the tumourbed after whole brain irradiation. Eight patients received local brain irradiation to the preoperative macroscopic tumourarea (de®ned as region of contrast enhancement) plus a 2cm safety-margin followed by a cone-down boost to the tumour-area only. In 19 patients the target-volume included the preoperative tumour-area and a 2-cm safety-margin and did not change throughout the therapy. The boost doses ranged from 10.8 to 26 Gy with an average of 20.1 Gy. The total doses ranged between 45 and 68 Gy with a median of 60 Gy. The overall median survival time was 12.5 month and did not vary signi®cantly between the three different treatment groups. 3.2. Localisation of the recurrence relative to the 90%isodose The graphical relation of the volume encompassed by the 90%-isodose for the smallest treatment volume (boost) to the recurrent tumour mass showed that (1) none of the 34 recurrent tumour were localised completely outside the 90%-isodose volume and (2) only one recurrence protruded outside the 90%-isodose. 3.3. 90%-isodose- and tumour-volumes The volumes of the 90%-isodose were between 109 and 845 ml with an average of 409 ml (median 408). The recurrent tumours showed volumes between 1 and 123 ml (average 23 ml, median 13 ml). The average recurrent-tumourvolume after tumour-resection with 18 ml was signi®cantly
56
U. Oppitz et al. / Radiotherapy and Oncology 53 (1999) 53±57
Fig. 2. Minimal distance between the 90%-isodose- and the recurrent tumour-surface (n 32), differential (hatched columns) and cumulative (dotted line).
smaller than after biopsy only which was 48 ml (P 0:017). There was no signi®cant difference in the size of the recurrence between completely and incompletely-resected tumours. The volume of the recurrent tumour did not correlate with survival. 3.4. Distance between the centres of gravity The distance between the centres of gravity of the volume encompassed by the 90%-isodose (treatment volume) and the recurrent tumour-volume were calculated and ranged between 0.4 and 3.4 cm with an average of 1.5 cm (median, 1.4 cm). 3.5. Minimal distance between the surface of the recurrenttumour volume and the 90%-isodose The minimal distance was calculated for all patients with tumours localised completely within the 90%-isodose (N 32) and ranged between 0 and 1.7 cm with an average of 0.5 cm (median 0.3 cm) (Fig. 2). For one patient the calculation was not feasible. There was no difference for the distance between the centres of gravity or the minimal surface distance between 90% isodose surface and the recurrence regardless whether the treatment volume was restricted to the size of the enhancing mass or allowed a 2-cm margin. 4. Discussion This study analyses the 3D tumour regrowth pattern in 34 patients with glioblastoma multiforme. A straightforward procedure was developed to reconstruct volumes of interest from different sets of CT-®lms and isodose plots allowing spatial correlation. Although modern 3D-treatment planning programs may offer anatomical matching tools for different data sets, the application to retrospective analyses of ®lm and paper based information is somewhat limited.
Other than Wallner et al. [23] and Liang et al. [11] we only included patients with histologically con®rmed WHO grade IV malignant gliomas in this study. They either received focal tumour irradiation throughout the entire irradiation or a WBI followed by a cone-down boost. With the help of a computer-program the position of the recurrent tumour was related to the 90%-isodose surface. The distances between the closest margin of the isodose line and the tumour and between the centres of gravity of both volumes were calculated. Even in the one patient in which the recurrent tumour surpasses the former 90%-isodose volume, the tumourvolume is still predominantly located within the region of maximal dosage and the centres of gravity of both volumes are very close. Both factors suggest that the tumourregrowth started within the area of maximal irradiation dose and in the centre of the chosen treatment volume. Similar to 14 other analysed individuals the above patient received a boost irradiation reduced to the former macroscopic tumour-area only. In the 19 other patients studied a 2 cm safety margin was added. The fact that we found only one tumour partially growing outside the treatment volume does not exclude that tumour-cells were situated within the peritumourous region and outside the high dose region but these were probably not the starting-point of tumour regrowth in the 34 patients analysed here. Lower doses covering this area may have been suf®cient to control low numbers of in®ltrating cells, although this remains hypothetical, especially because of the steep craniocaudal dose gradient outside the treatment volume (coplanar treatment techniques). Our results agree with the ®ndings of other groups [11,23], with 33/34 patients we demonstrate even higher local-failure rates. We conclude that the recurrent-tumourgrowth does not seem to be caused by insuf®cient treatment volumes and close margins but rather be result of doses which are too low to maintain a long-term tumour-control. Our ®ndings suggest a dose escalation to restricted volumes in postoperative treatment of glioblastomas. Walker et al. [22] and the Brain Tumour Study Group (BTSG) [17] showed that a dose increase to 60 Gy and more is tolerable without severe normal brain damage. In the fundamental high dose study by Salazar et al. 1979 and the BTSG [16] a signi®cantly longer median survival of the very high -group compared to the conventionally treated group was demonstrated (56 vs. 30 weeks). An altered fractionation-scheme with different end-doses were tested by Nelson et al. They treated GBM patients with 1.2 Gy twice a day combined with chemotherapy (Bis-chlorethylnitrosourea (BCNU)) to doses between 64.8±81.6 Gy and found the longest median survival of 12.8 month at 72 Gy [12]. Results from two recent high dose studies with a total dose of 90 Gy photon [14,20] or combined proton/photon irradiation [4] do show a survival bene®t but even at that dose treatment failure still seems to remain locally. Alternative ways of dose escalation such as interstitial
U. Oppitz et al. / Radiotherapy and Oncology 53 (1999) 53±57
brachytherapy [19] and stereotactic radiosurgery [15] may prolong median survival in a certain patient group but have to be evaluated in larger prospective studies like the radiosurgery boost trial initiated by the EORTC [3].
[12]
References
[13]
[1] Bleehen NM, Stenning SP. A medical research council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. Br. J. Cancer 1991;64:769±774. [2] Burger PC, Heinz RE, Shibata T, Kleihues P. Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J. Neurosurg. 1988;68:698±704. [3] EORTC 22972: Focal fractionated conformal stereotactic boost following conventional radiotherapy of high grade gliomas: A randomised phase III study, 1998. [4] Fitzek M, Thornton A, Rabenow J, et al. Results of 90 Gy proton/ photon radiation therapy for glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 1997;39(10):139. [5] Garden AS, Maor MH, Yung WKA, et al. Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas. Radiother. Oncol. 1991;20:99±110. [6] Gross MW, Weber WA, Feldmann HJ, Bartenstein P, Schwaiger M, Molls M. The value of F-18-¯uorodeoxyglucose PET for the 3-D radiation treatment planning of malignant gliomas. Int. J. Radiat. Oncol. Biol. Phys. 1998;41:989±995. [7] Halperin EC, Bentel G, Heinz ER, Burger PC. Radiation therapy treatment planning in supratentorial glioblastoma multiforme: an analysis based on post mortem topographic anatomy with CT correlations. Int. J. Radiat. Oncol. Biol. Phys. 1989;17:1347±1350. [8] Halperin EC, Burger PC, Bullard DE. The fallacy of the localized supratentorial malignant glioma. Int. J. Radiat. Oncol. Biol. Phys. 1988;15:505±509. [9] Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30:907±911. [10] Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ. Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J. Neurosurg. 1987;66:865±874. [11] Liang BC, Thornton AF, Sandler HM, Greenberg HS. Malignant
[14] [15]
[16] [17] [18] [19] [20] [21] [22] [23]
57
astrocytomas: focal tumour recurrence after external beam radiation therapy. J. Neurosurg. 1991;75:559±563. Nelson DF, Curran WJ, Scott C, et al. Hyperfractionated radiation therapy and bis.chlorethyl nitrosourea in the treatment of malignant glioma ± possible advantage observed at 72.0 Gy in 1.2 Gy b.i.d. fractions: report of the radiation therapy oncology group protocol 8302. Int. J. Radiat. Oncol. Biol. Phys. 1993;25:193±207. Onoyama Y, Abe M, Yabumoto E, Sakamoto T, Nishidai T. Radiation therapy in the treatment of glioblastoma. Am. J. Roentgenol. 1976;126:481±492. Radany EH, Sandler HM, Ten Haken RK, et al. 3D conformal radiotherapy for malignant astrocytomas: dose escalation to 90 Gy. Int. J. Radiat. Oncol. Biol. Phys. 1997;39(11):140. Sakaria JN, Mehta MP, Loef¯er JS, et al. Radiosurgery in the initial management of malignant gliomas: survival comparison with RTOG recursive partitioning analysis. Int. J. Radiat. Oncol. Biol. Phys. 1995;32:931±941. Salazar OM, Rubin P, Feldstein ML, Pizzutiello R. High dose radiation therapy in the treatment of malignant gliomas: ®nal report. Int. J. Radiat. Oncol. Biol-Phys. 1979;5:1733±1740. Salazar OM, Rubin P, McDonald JV, Feldstein ML. High dose radiation therapy in the treatment of glioblastoma multiforme: a preliminary report. Int. J. Radiat. Oncol. Biol. Phys. 1976;1:717±727. Salazar OM, Rubin P, McDonald JV, Feldstein ML. Patterns of failure in intracranial astrocytomas after irradiation: analysis of dose and ®eld factors. Am. J. Roentgenol. 1976;126:279±292. Scharfen CO, Sneed PK, Wara WM, et al. High activity iodine-125 interstitial implant for gliomas. Int. J. Radiat. Oncol. Biol. Phys. 1992;24:583±591. Seither RB, Jose B, Paris KJ, Lindberg RD, Spanos WJ. Results of irradiation in patients with high-grade gliomas evaluated by magnetic resonance imaging. Am. J. Clin. Oncol. 1995;18:297±299. Walker MD, Alexander Jr E, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J. Neurosurg. 1978;49:333±343. Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int. J. Radiat. Oncol. Biol. Phys. 1979;5:1725±1731. Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int. J. Radiat. Oncol. Biol. Phys. 1989;16:1405±1409.
Short communication
www.elsevier.com/locate/radonline
3D-recurrence-patterns of gliobastomas after CT-planned postoperative irradiation Ulrich Oppitz*, Dirk Maessen, Hildegard Zunterer, Susanne Richter, Michael Flentje Department of Radiation Oncology, University of WuÈrzburg, Josef-Schneider-Strasse 11, 97080 WuÈrzburg, Germany Received 13 August 1998; received in revised form 16 July 1999; accepted 23 July 1999
Abstract Background and purpose: The introduction of computed-tomography as an advanced planning tool for the irradiation of intracranial tumours led to a controversial discussions about the optimal target-volume for the primary and postoperative treatment of malignant gliomas. This study analyses the three-dimensional tumour regrowth pattern relative to the treated volume which included the macroscopic preoperative tumour and 2-cm safety margin. Materials and methods: Seventy-nine patients with histologically-con®rmed Glioblastoma multiforma and documented recurrence who were irradiated in our department between 1990 and 1996 were reviewed. With the help of a computer program written for this purpose, the PTV of the CT-based treatment plan was reconstructed and its spatial outline compared with the reconstructed volume of the recurrent tumour in the control CT-study. Results: In 33 out 34 patients for which the CT-study showing tumour-recurrence was available the recurrence was completely situated within the original 90%-isodose. Only one tumour surpassed the outside surface of the PTV but was predominantly situated within the original tumourbed and suggests a tumour-regrowth within the high dose volume. Conclusions: The above results show that target-volumes based on the preoperative size of the enhanced tumour mass well cover the site of recurrence in nearly all cases. The ®ndings suggest dose escalation to a more restricted volume. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Malignant gliomas; Radiotherapy; CT-Planning; Recurrence-pattern
1. Introduction The diagnosis of malignant glioma is usually associated with a poor prognosis. Median survival after surgical resection with no further treatment is about 14 weeks. Postoperative whole brain irradiation (WBI) increased the median survival to 35 weeks in prospectively controlled trials [21,13]. After the introduction of computed-tomography as a planning tool for the irradiation of intracranial tumours, many authors tried to de®ne the optimal treatment-volume for the primary and postoperative treatment of malignant gliomas. Contrary to earlier assumptions [18], Hochberg and Pruitt [9] reported in 1980, that 80% of glioblastomas recurred completely and 10% partially within the original tumoursite and that multicentricity was a rather uncommon phenomenon. Wallner et al. [23] superimposed anatomically corresponding CT images of the largest preoperative and recur* Corresponding author.
rent tumour areas and found that 78 % of the recurrences were localised within a 2.0-cm margin of the initial tumour bed. In contradiction to these ®ndings suggesting the introduction of localised brain irradiation as a standard treatment procedure, major studies by Kelly et al. [10], Burger et al. [2] and Halperin et al. [7] reported that atypical cells may surpass the perifocal edematous area, which is usually de®ned water by neuroradiologists. They came to the conclusion that a 2±3 cm safety-margin around the contrast-enhancing tumour-area will often underestimate the spread of the neoplasm. Halperin et al. [8] state that `only portals which encompassed the peritumoural edema and a 3 cm safety-margin around the edema adequately covered the histologically identi®ed tumour', the missed microscopic tumour in®ltrations may be the cause of treatment failure if the bulky area could be controlled. This led to considerable uncertainties concerning the optimal target volume in the postoperative treatment of glioblastoma multiforme (GBM). The margins of the planning target volume vary quite signi®cantly between different institutions. The safety zone around the preoperative contrast-
0167-8140/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0167-814 0(99)00117-6
54
U. Oppitz et al. / Radiotherapy and Oncology 53 (1999) 53±57
enhancing tumour ranged between 1±4 cm [1,5,11,23] up to the complete peritumoural edema 1 2±3 cm safety margin [20]. It is the aim of this study to analyse the localisation and 3D patterns of tumour recurrences after the introduction of a CT-based 3D-treatment planning concept and limited volume irradiation in the treatment of malignant gliomas.
ted volume limited to the preoperative contrast-enhancing tumour-area only. The patients were irradiated with 60Co and/or 5 MV-photons in a multiple-®eld-technique with single fractions ranging from 1.8 to 3.0 Gy (median, 2.0 Gy). The majority of the patients (74.6%) received one fraction a day, 25.4% were irradiated twice a day, ten times a week with single fractions of 1.8 Gy up to a total dose of 54 Gy.
2. Materials and methods Our treatment-strategy for GBM changed gradually from WBI to a localised 3D CT-planned irradiation in 1989. Records were reviewed from 79 patients with histological con®rmed Glioblastoma multiforme (WHO grade IV) and documented tumour recurrence who were irradiated in the Deptartment of Radiation Oncology, University of WuÈrzburg between 1990 and 1996. Six patients had to be excluded from further analysis because of following criteria of exclusion: age , 18 years, whole brain irradiation (WBI) only, total dose below 40 Gy and multilocular growth with more than one target-volume. The age at time of diagnosis ranged between 24 and 75 years, with a median age of 57 years. Forty three (59%) were under and 30 (41%) above 60 years of age. There were 30 female (41%) and 43 (59%) male patients. Thirty four of the tumours were situated in the right, 30 in the left and three in both hemispheres, six pretherapeutic CTstudies were not available. Twenty-four percent of the surgical procedures were biopsies only (of which 87% were stereotactic) and 76% were resections, 25% gross total excisions and 75% subtotal resections, in one patient the extent of surgery could not be determined. Four patients were lost from follow-up. In 34 patients complete CT information (preoperative CT, planning CT with 3D-dose-representation and CT and time of progression) was available for the 3D-recurrence pattern analyses. These patients formed the base of the study. No signi®cant differences for age at diagnosis, dosage, treatment technique, primary tumour-volume, follow-uptime and survival between the study group and the whole collective was detected. 2.1. Radiation therapy The postoperative radiation treatment included CT-based geometrical 3D-treatment planning of a target-volume which included the preoperative contrast-enhancing tumour-volume in every case. In most cases a cone down technique was used. The initial treated volume either enclosed the whole brain (WBI) with a boost irradiation to the gross tumour volume or included the preoperative contrast-enhancing macroscopic tumour-volume and a 2 cm safety margin. Depending on the size of the tumour it was either irradiated in this manner throughout the whole treatment or was followed by boost-irradiation with a trea-
2.2. Reconstruction of the volume encompassed by the 90%isodose (treated volume) The CT-based treatment plan was the starting point for de®nition of a co-ordinate-system for the spatial outline of the 90%-isodose. If the treatment was performed as a cone down in two series the 90% isodose of the boost series was used for this analysis. The volume encompassed by the 90%-isodose-surface was considered the treated volume. The origins of the x- and y-axis were de®ned by the isocentre of the plan. The 0-value of the z-axis was centred between the most cranial and caudal CT-scan of the irradiation volume. A polygon was ®tted to the outline of the 90%isodose in each CT-slice. For every point describing the polyeder the x-,y- and z-co-ordinate relative to the origin was measured. 2.3. Volume-reconstruction of the tumour-recurrence A new contrast-enhancing structure after complete extirpation or regrowth of residual tumour after partial resection with clinical or radiological con®rmation in further follow up were de®ned as tumour-recurrence. Positron emission tomographic (PET)-scanning which is helpful to differentiate between recurrent tumour and radiation necrosis [6] was not available at that time. For the reconstruction of the recurrent-tumour volume and projection into the former treatment-plan the co-ordinate system of the treatment-planning CT had to be transferred to the CT-scan demonstrating the recurrent tumour. For this purpose the z-axis had to be marked in the scout of the planning-CT. Afterwards the 0coordinate of the z-axis was transferred from this scout to the scout of the new CT using a subtrascope (Siemens, an instrument originally developed for superimposing diagnostic X-ray images, a precursor of digital subtraction angiography) under consideration of possible differences in head inclination between the two CT-examinations. This de®ned a horizontal central plane identical to the treatment set-up. Then the origin of the co-ordinate-system (isocentre of the treatment plan) was transferred to the new CT using relations to anatomical landmarks and projected to all CT-slices (vertical central plane) showing recurrent tumour. Now the recurrent-tumour-volume was reconstructed identical to the procedure described above for the volume encompassed by the 90%-isodose.
U. Oppitz et al. / Radiotherapy and Oncology 53 (1999) 53±57
55
Fig. 1. (a) Example of a recurrent tumour completely localised within the volume of the 90%-isodose from three different viewpoints. (b) Example of the recurrent tumour partially surpassing the volume of the 90%-isodose from three different viewpoints.
2.4. Relationship between 90%-isodose- surface and recurrent-tumour volume With the help of a computer program (based on Mathematica TM) written for this purpose the volume encompassed by the 90%-isodose and a 3D-reconstruction of the recurrent-tumour were calculated using the common origin of the co-ordinate systems and the angulation resulting from different head inclinations in the planning CT and the CTstudy showing recurrence. The surface of each polygon was calculated and multiplied by the thickness of the CT-slice for volume determination. Then both volumes were projected into each other using the co-ordinate system as described before. For both volumes the centres of gravity and its distance were calculated. The calculations were rechecked with the help of the graphical reconstructions of the tumour-recurrence and the treated volume from three different viewpoints (vp) (Fig. 1a,b). Finally the closest distance between the outmost border of the recurrent tumour and the 90%-isodose was determined.
3. Results 3.1. Patients treatment In 34 cases post-treatment CT-scans with recurrent tumour were available for analysis. Clinical deterioration was the reason for these CT's in all cases. The postoperative irradiation of the patients was not homogeneous. Seven
patients received a cone-down boost to the tumourbed after whole brain irradiation. Eight patients received local brain irradiation to the preoperative macroscopic tumourarea (de®ned as region of contrast enhancement) plus a 2cm safety-margin followed by a cone-down boost to the tumour-area only. In 19 patients the target-volume included the preoperative tumour-area and a 2-cm safety-margin and did not change throughout the therapy. The boost doses ranged from 10.8 to 26 Gy with an average of 20.1 Gy. The total doses ranged between 45 and 68 Gy with a median of 60 Gy. The overall median survival time was 12.5 month and did not vary signi®cantly between the three different treatment groups. 3.2. Localisation of the recurrence relative to the 90%isodose The graphical relation of the volume encompassed by the 90%-isodose for the smallest treatment volume (boost) to the recurrent tumour mass showed that (1) none of the 34 recurrent tumour were localised completely outside the 90%-isodose volume and (2) only one recurrence protruded outside the 90%-isodose. 3.3. 90%-isodose- and tumour-volumes The volumes of the 90%-isodose were between 109 and 845 ml with an average of 409 ml (median 408). The recurrent tumours showed volumes between 1 and 123 ml (average 23 ml, median 13 ml). The average recurrent-tumourvolume after tumour-resection with 18 ml was signi®cantly
56
U. Oppitz et al. / Radiotherapy and Oncology 53 (1999) 53±57
Fig. 2. Minimal distance between the 90%-isodose- and the recurrent tumour-surface (n 32), differential (hatched columns) and cumulative (dotted line).
smaller than after biopsy only which was 48 ml (P 0:017). There was no signi®cant difference in the size of the recurrence between completely and incompletely-resected tumours. The volume of the recurrent tumour did not correlate with survival. 3.4. Distance between the centres of gravity The distance between the centres of gravity of the volume encompassed by the 90%-isodose (treatment volume) and the recurrent tumour-volume were calculated and ranged between 0.4 and 3.4 cm with an average of 1.5 cm (median, 1.4 cm). 3.5. Minimal distance between the surface of the recurrenttumour volume and the 90%-isodose The minimal distance was calculated for all patients with tumours localised completely within the 90%-isodose (N 32) and ranged between 0 and 1.7 cm with an average of 0.5 cm (median 0.3 cm) (Fig. 2). For one patient the calculation was not feasible. There was no difference for the distance between the centres of gravity or the minimal surface distance between 90% isodose surface and the recurrence regardless whether the treatment volume was restricted to the size of the enhancing mass or allowed a 2-cm margin. 4. Discussion This study analyses the 3D tumour regrowth pattern in 34 patients with glioblastoma multiforme. A straightforward procedure was developed to reconstruct volumes of interest from different sets of CT-®lms and isodose plots allowing spatial correlation. Although modern 3D-treatment planning programs may offer anatomical matching tools for different data sets, the application to retrospective analyses of ®lm and paper based information is somewhat limited.
Other than Wallner et al. [23] and Liang et al. [11] we only included patients with histologically con®rmed WHO grade IV malignant gliomas in this study. They either received focal tumour irradiation throughout the entire irradiation or a WBI followed by a cone-down boost. With the help of a computer-program the position of the recurrent tumour was related to the 90%-isodose surface. The distances between the closest margin of the isodose line and the tumour and between the centres of gravity of both volumes were calculated. Even in the one patient in which the recurrent tumour surpasses the former 90%-isodose volume, the tumourvolume is still predominantly located within the region of maximal dosage and the centres of gravity of both volumes are very close. Both factors suggest that the tumourregrowth started within the area of maximal irradiation dose and in the centre of the chosen treatment volume. Similar to 14 other analysed individuals the above patient received a boost irradiation reduced to the former macroscopic tumour-area only. In the 19 other patients studied a 2 cm safety margin was added. The fact that we found only one tumour partially growing outside the treatment volume does not exclude that tumour-cells were situated within the peritumourous region and outside the high dose region but these were probably not the starting-point of tumour regrowth in the 34 patients analysed here. Lower doses covering this area may have been suf®cient to control low numbers of in®ltrating cells, although this remains hypothetical, especially because of the steep craniocaudal dose gradient outside the treatment volume (coplanar treatment techniques). Our results agree with the ®ndings of other groups [11,23], with 33/34 patients we demonstrate even higher local-failure rates. We conclude that the recurrent-tumourgrowth does not seem to be caused by insuf®cient treatment volumes and close margins but rather be result of doses which are too low to maintain a long-term tumour-control. Our ®ndings suggest a dose escalation to restricted volumes in postoperative treatment of glioblastomas. Walker et al. [22] and the Brain Tumour Study Group (BTSG) [17] showed that a dose increase to 60 Gy and more is tolerable without severe normal brain damage. In the fundamental high dose study by Salazar et al. 1979 and the BTSG [16] a signi®cantly longer median survival of the very high -group compared to the conventionally treated group was demonstrated (56 vs. 30 weeks). An altered fractionation-scheme with different end-doses were tested by Nelson et al. They treated GBM patients with 1.2 Gy twice a day combined with chemotherapy (Bis-chlorethylnitrosourea (BCNU)) to doses between 64.8±81.6 Gy and found the longest median survival of 12.8 month at 72 Gy [12]. Results from two recent high dose studies with a total dose of 90 Gy photon [14,20] or combined proton/photon irradiation [4] do show a survival bene®t but even at that dose treatment failure still seems to remain locally. Alternative ways of dose escalation such as interstitial
U. Oppitz et al. / Radiotherapy and Oncology 53 (1999) 53±57
brachytherapy [19] and stereotactic radiosurgery [15] may prolong median survival in a certain patient group but have to be evaluated in larger prospective studies like the radiosurgery boost trial initiated by the EORTC [3].
[12]
References
[13]
[1] Bleehen NM, Stenning SP. A medical research council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. Br. J. Cancer 1991;64:769±774. [2] Burger PC, Heinz RE, Shibata T, Kleihues P. Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J. Neurosurg. 1988;68:698±704. [3] EORTC 22972: Focal fractionated conformal stereotactic boost following conventional radiotherapy of high grade gliomas: A randomised phase III study, 1998. [4] Fitzek M, Thornton A, Rabenow J, et al. Results of 90 Gy proton/ photon radiation therapy for glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 1997;39(10):139. [5] Garden AS, Maor MH, Yung WKA, et al. Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas. Radiother. Oncol. 1991;20:99±110. [6] Gross MW, Weber WA, Feldmann HJ, Bartenstein P, Schwaiger M, Molls M. The value of F-18-¯uorodeoxyglucose PET for the 3-D radiation treatment planning of malignant gliomas. Int. J. Radiat. Oncol. Biol. Phys. 1998;41:989±995. [7] Halperin EC, Bentel G, Heinz ER, Burger PC. Radiation therapy treatment planning in supratentorial glioblastoma multiforme: an analysis based on post mortem topographic anatomy with CT correlations. Int. J. Radiat. Oncol. Biol. Phys. 1989;17:1347±1350. [8] Halperin EC, Burger PC, Bullard DE. The fallacy of the localized supratentorial malignant glioma. Int. J. Radiat. Oncol. Biol. Phys. 1988;15:505±509. [9] Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30:907±911. [10] Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ. Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J. Neurosurg. 1987;66:865±874. [11] Liang BC, Thornton AF, Sandler HM, Greenberg HS. Malignant
[14] [15]
[16] [17] [18] [19] [20] [21] [22] [23]
57
astrocytomas: focal tumour recurrence after external beam radiation therapy. J. Neurosurg. 1991;75:559±563. Nelson DF, Curran WJ, Scott C, et al. Hyperfractionated radiation therapy and bis.chlorethyl nitrosourea in the treatment of malignant glioma ± possible advantage observed at 72.0 Gy in 1.2 Gy b.i.d. fractions: report of the radiation therapy oncology group protocol 8302. Int. J. Radiat. Oncol. Biol. Phys. 1993;25:193±207. Onoyama Y, Abe M, Yabumoto E, Sakamoto T, Nishidai T. Radiation therapy in the treatment of glioblastoma. Am. J. Roentgenol. 1976;126:481±492. Radany EH, Sandler HM, Ten Haken RK, et al. 3D conformal radiotherapy for malignant astrocytomas: dose escalation to 90 Gy. Int. J. Radiat. Oncol. Biol. Phys. 1997;39(11):140. Sakaria JN, Mehta MP, Loef¯er JS, et al. Radiosurgery in the initial management of malignant gliomas: survival comparison with RTOG recursive partitioning analysis. Int. J. Radiat. Oncol. Biol. Phys. 1995;32:931±941. Salazar OM, Rubin P, Feldstein ML, Pizzutiello R. High dose radiation therapy in the treatment of malignant gliomas: ®nal report. Int. J. Radiat. Oncol. Biol-Phys. 1979;5:1733±1740. Salazar OM, Rubin P, McDonald JV, Feldstein ML. High dose radiation therapy in the treatment of glioblastoma multiforme: a preliminary report. Int. J. Radiat. Oncol. Biol. Phys. 1976;1:717±727. Salazar OM, Rubin P, McDonald JV, Feldstein ML. Patterns of failure in intracranial astrocytomas after irradiation: analysis of dose and ®eld factors. Am. J. Roentgenol. 1976;126:279±292. Scharfen CO, Sneed PK, Wara WM, et al. High activity iodine-125 interstitial implant for gliomas. Int. J. Radiat. Oncol. Biol. Phys. 1992;24:583±591. Seither RB, Jose B, Paris KJ, Lindberg RD, Spanos WJ. Results of irradiation in patients with high-grade gliomas evaluated by magnetic resonance imaging. Am. J. Clin. Oncol. 1995;18:297±299. Walker MD, Alexander Jr E, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J. Neurosurg. 1978;49:333±343. Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int. J. Radiat. Oncol. Biol. Phys. 1979;5:1725±1731. Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int. J. Radiat. Oncol. Biol. Phys. 1989;16:1405±1409.