Interstitial 125I radiosurgery of supratentorial de novo WHO Grade 2 astrocytoma and oligoastrocytoma in adults
Long-term results and prognostic factors
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Abstract
BACKGROUND
Detailed long-term outcome data are not available for adult patients with World Health Organization (WHO) Grade 2 astrocytoma or oligoastrocytoma.
METHODS
A previously published short-term data set of 239 adult patients with circumscribed de novo supratentorial astrocytoma (187 patients) and oligoastrocytoma (52 patients) treated with interstitial iodine-125 (125I) radiosurgery as primary treatment (1979–1992) was revisited. Survival, progression-free survival, functionally independent survival, postrecurrence survival, and time to malignant transformation were estimated with the Kaplan–Meier method. Prognostic factors were obtained from the Cox multivariate proportional hazards model.
RESULTS
Five-, 10-, and 15-year survival was 56%, 37%, and 26%, respectively (median follow-up, 10.3 yrs). Progression-free survival was 45%, 21%, and 14%, respectively. The corresponding malignant transformation rates were 33%, 54%, and 67%. No leveling off of the Kaplan–Meier curves could be observed for any of the chosen endpoints. Age > 50 years, a tumor volume > 20 mL, and/or a Karnofsky score ≤ 80 were associated with decreased survival or progression-free survival. Age > 35 years and/or a tumor volume > 20 mL increased risk of malignant transformation. Prognostic factors determined subsets of patients with 10-year survival ranging from as low as 6% to as high as 55% and progression-free survival ranging 1–31%.
CONCLUSIONS
Long-term tumor stabilization is rare. As outcome is mainly determined by treatment-independent factors, minimization of any treatment-related risk must be considered essential. Cancer 2006. © 2006 American Cancer Society.
The long-term prognosis of adult patients with supratentorial World Health Organization (WHO) Grade 2 glioma treated during the computed tomography (CT) era remains indistinct. Most studies, so far, have referred to a median follow-up period in the range of 5–6 years, and detailed outcome data have not been reported. These studies have, in addition, been biased by poorly defined selection criteria such as histology (e.g., inclusion of oligodendroglioma or pilocytic astrocytoma), tumor location (e.g., infratentorial tumors), age (e.g., inclusion of children), and applied treatment strategy. This has led to divergent conclusions regarding long-term prognosis with 10-year survival rates ranging from as low as 20% to as high as 70%.1-9
The current retrospective long-term analysis presents, for the first time, detailed outcome data (adjusted for effects of prognostic factors) for a large and homogeneous adult patient subpopulation with circumscribed de novo supratentorial nongemistocytic, WHO Grade 2 astrocytoma and oligoastrocytoma undergoing interstitial 125I radiosurgery as primary treatment. Our previously published data was revisited, and the median follow-up for survivors has been increased from 4.5 to more than 10 years.5 The aims of the present study were to describe the long-term behavior of this complex tumor entity in detail and to bring potential risks and benefits of the applied treatment strategy into perspective concerning overall prognosis.
MATERIALS AND METHODS
Between 1979 and 1992, 594 patients with WHO Grade 1 and Grade 2 glioma were treated with 125I implants at the Department of Stereotactical Neurosurgery in Freiburg. Diagnosis was obtained by CT-guided stereotactic biopsy. Pediatric patients and patients with infratentorial tumor location, WHO Grade 1 pilocytic astrocytoma, WHO Grade 2 ependymoma, oligodendroglioma, or gemistocytic astrocytoma were excluded. Gemistocytic astrocytomas are associated with more malignant behavior and should be analyzed separately as demonstrated elsewhere.4, 10 Thus, 306 adults (aged ≥ 18 yrs) had supratentorial tumors that were classified as WHO Grade 2 astrocytoma or oligoastrocytoma.11, 12 It was assumed that these 2 tumor entities did not differ significantly in terms of prognosis and length of survival after implant therapy. This assumption was supported by our previous work.5 To make the patient population as homogeneous as possible, pretreated patients (surgery and/or radiotherapy [RT]; n = 57) were excluded. Eight patients were lost to follow-up, and 2 patients died perioperatively. Thus, this series comprised 239 adult patients with de novo, supratentorial, WHO Grade 2 astrocytoma (n = 187) or oligoastrocytoma (n = 52).
Indication for Interstitial Radiosurgical Treatment
Interstitial radiosurgery was indicated for patients with 1) a documented progression of clinical symptoms and/or computerized tomography (CT) and magnetic resonance (MR) imaging findings; 2) a minimum Karnofsky performance scale (KPS) score of 70, and 3) a circumscribed tumor with a diameter not exceeding 5 cm on CT or MR scan.13 Patients with noncircumscribed (diffuse) tumors or with tumors infiltrating the corpus callosum were excluded. Development of new symptoms (e.g., seizures), and/or increase in seizure frequency, and/or any enlargement of the tumor were classified as clinical or neuroradiologic tumor progression. For asymptomatic patients who showed unchanged tumor volumes over time, a wait-and-see attitude was preferred. From 1979–1985, interstitial radiosurgery was performed only for tumors at locations difficult to access by open microsurgical treatment. After 1985, interstitial radiosurgery was used more often as a treatment alternative to microsurgery.
Biopsy Technique and Implantation
The authors have described the stereotactic technique of biopsy and implantation in several previously published reports.4, 5, 14, 15 Briefly, biopsy was performed using a modification of the Riechert headring under CT guidance along a trajectory from the periphery throughout the tumor. The histologic diagnosis was made by the attending neuropathologist on the basis of the intraoperative analysis of smear preparations and postoperative examination of paraffin-embedded material. Low-activity 125I seeds exclusively were used in this series. Permanent implants were preferred between 1979 and 1985, and temporary implants thereafter. The applied median reference dose (calculated to the outer rim of the tumor) was 60 Grays (Gy) for temporary implants and 100 Gy for permanent implants; Details of treatment (tumor dose, dose rate, mode of implantation) were not influenced by tumor location and tumor size. The dose rate calculated to the outer rim of the tumor was low (median, 8 centiGy/h for temporary implants). The biologically effective dose has been judged to be very similar for both temporary and permanent implants.16
Patient Evaluation
Clinical and neuroradiologic follow-up examination was performed 3 months postoperatively, followed by 6-month intervals (until last follow-up). The Karnofsky Performance Score (KPS) was used for clinical evaluation. The patient's posttreatment time spent with a KPS of at least 70 was defined as functionally independent survival. The time interval between tumor progression and death or last follow-up evaluation was used for estimation of postrecurrence survival. An accurate tumor volume calculation was possible by volumetry of the isodose curves of the reference dose, as described previously.16 Computerized tomographic volumetry of tumor size for follow-up evaluation was performed by using the formula for an ellipsoid or a sphere. The treatment response was assessed according to McDonald criteria.17 In a complete response, any appearance of a new lesion was suspicious for tumor recurrence. Stereotactic biopsy was performed in all these patients for verification of tumor progress and/or recurrence. Criteria for malignant transformation have been described previously.4, 5 In brief, these are 1) tumor histology reclassified as WHO Grade 3 or 4 after rebiopsy or open surgery, or 2) multilocular growth or new contrast enhancement of an initially hypointense tumor accompanied by increase in tumor size after complete regression of irradiation sequelae.
Statistical Analysis
The reference point for this study was the date of the implantation procedure. The date of last follow-up was April 2000. Endpoints were death, date of tumor progression, date of significant clinical deterioration (KPS < 70), and date of malignant transformation. Survival, time to tumor progression, time to malignant transformation, functionally independent survival, time to additional external-beam irradiation or open surgery, and postrecurrence survival were analyzed with the Kaplan–Meier method.18 The ratios number of patients at risk divided by the number of events per 5-year time intervals were calculated and compared. In case of a significant increase of this ratio (compared with the preceding 5-yr time interval), a stabilization (leveling off) of the curve was assumed. Prognostic factors were obtained from the multivariate hazards model, and adjusted Kaplan–Meier curves were generated.19 All variables tested in prognostic models are given in Table 1. The correlation between prognostic factors was analyzed by using the chi-square statistic. First, univariate analysis was performed by using each of the variables. Second, variables that appeared important from step one (significant at the 0.05 level) were fitted together. When interrelations between variables occurred, alternative models were tested. Comparison of alternative models was performed by computing the maximized likelihood. The “BEST” model contained only variables that were significantly associated with the chosen endpoints after adjustment for effects of other variables in the model.
| Factors | Variable |
|---|---|
| Gender | Male or female |
| Age | ≤50 yrs or >50 yrs |
| KPS | < 90 or ≥90 |
| Duration of symptoms | ≤6 mos or > 6 mos |
| First symptom | |
| Seizures | Yes or no |
| Paresis | Yes or no |
| CT characteristics | Contrast enhancement, yes or no |
| Tumor volume | ≤20 mL or > 20 mL |
| Tumor location | Lobar or nonlobar |
| Midline shift | Yes or no |
| Mode of implantation | Temporary or permanent |
| Tumor histology | Astrocytoma or oligoastrocytoma |
| Treatment date | ≤1986 or > 1986 |
- KPS: Karnofsky performance score.
RESULTS
Patient Characteristics
This series was comprised of a selected, homogeneously treated population of 239 patients with a median age of 37 years (range, 18–71 yrs) at the time of implantation and a median follow-up period of 10.3 years for survivors (range, 8 –21.3 yrs). Men predominated (142 men, 97 women) and were younger (median age, 34 vs. 38 yrs, P > 0.05). Left-sided tumors were seen in 97 patients. The distribution of clinical and radiologic parameters is summarized in Tables 2 and 3. Conventionally fractionated limited-field external-beam radiation with a tumor dose in the range of 50–60 Gy was initiated in 109 patients at the time of tumor progression or malignant transformation. A reimplantation of 125I seeds was performed in 21 patients because of small tumor recurrences. The estimated probability to receive additional external-beam irradiation after 5 and 10 years was 39% and 59%, respectively.
| Variables | Mean/median (SD) |
|---|---|
| Age at time of implant, yrs | 37/37 (12) |
| Karnofsky performance score | 85/90 (8) |
| Duration of symptoms, mos | 21/7 (32) |
| Tumor volume, mL | 23/16 (22) |
| Covariate | No. | % 5-yr survival | % 10-yr survival | P |
|---|---|---|---|---|
| Gender | 0.93 | |||
| Male | 142 | 55 | 35 | |
| Female | 97 | 57 | 35 | |
| Age | 0.001 | |||
| < 50 yrs | 196 | 62 | 40 | |
| ≥50 yrs | 43 | 39 | 23 | |
| KPS score | 0.0003 | |||
| ≥ 90 | 146 | 67 | 44 | |
| < 90 | 93 | 43 | 26 | |
| Symptom duration | 0.27 | |||
| > 6 mos | 131 | 66 | 43 | |
| ≤6 mos | 108 | 47 | 28 | |
| Symptoms | ||||
| Seizure | 0.009 | |||
| Seizure | 189 | 61 | 37 | |
| No seizure | 50 | 37 | 23 | |
| Paresis | 0.0001 | |||
| Paresis | 46 | 26 | 9 | |
| No paresis | 193 | 63 | 40 | |
| CT characteristics | 0.0007 | |||
| Enhanced | 43 | 31 | 21 | |
| Not enhanced | 196 | 61 | 38 | |
| Tumor volume | 0.0003 | |||
| >20 ccm | 149 | 68 | 44 | |
| ≤20 ccm | 90 | 41 | 24 | |
| Tumor location | 0.015 | |||
| Lobar | 136 | 65 | 42 | |
| Nonlobar | 103 | 44 | 27 | |
| Midline shift | 0.0001 | |||
| Yes | 59 | 30 | 14 | |
| No | 180 | 65 | 43 | |
| Mode of implantation | 0.27 | |||
| Temporary | 136 | 62 | 37 | |
| Permanent | 103 | 49 | 34 | |
| Histology | 0.4 | |||
| Oligoastrocytoma | 52 | 52 | 33 | |
| Astrocytoma | 187 | 57 | 36 | |
| Treatment date | 0.2 | |||
| ≤ 1986 | 85 | 51 | 34 | |
| > 1986 | 154 | 62 | 39 |
Perioperative Mortality and Morbidity
Perioperative mortality was 0.8% (Two patients were excluded from further analysis.). Perioperative transient morbidity was 1.2% (3 patients).
Overall Survival, Functionally Independent Survival
At the time of last follow-up, 154 patients had died. Death was tumor-related in all patients. Five-year, 10-year, and 15-year survival rates were 56%, 37%, and 26%, respectively (Fig. 1). No leveling off of the survival curve was seen over time. Forty-nine patients survived more than 10 years, and 38 of these long-term survivors were still alive at the time of last follow-up. The rates of functionally independent patients after 5, 10, and 15 years were 51%, 32%, and 22% (Fig. 1).
Kaplan–Meier curves showing overall, functionally independent, and progression-free survival rates for 239 patients with World Health Organization (WHO) Grade 2 astrocytoma–oligoastrocytoma.
Progression-Free Survival, Postrecurrence Survival
A total of 193 patients exhibited tumor progression or recurrence. Five-, 10-, and 15-year progression-free survival was 45%, 21%, and 14% (Fig. 1), and no plateau of the Kaplan–Meier curve was observed. At 5- and 10-years, postrecurrence survival was 21% and 8%, respectively (Fig. 2).
Kaplan–Meier curves showing postrecurrence survival rates. The unfavorable impact of malignant transformation is demonstrated.
Long-Term Progression-Free Survival
Thirty-one patients showed a progression-free survival of more than 10 years, and no signs of tumor progression could be detected in 22 of 31 patients at the time of last follow-up; Median follow-up of this most favorable subgroup population with long-term tumor stabilization was 162 months (range, 125–244 mos). These patients were 38 years of age (median) at time of presentation, 49.8 years (median) at last follow-up, had small tumors (median tumor volume, 16.8 mL), and had high performance scores before treatment (median KPS, 90) and at last follow-up (median KPS, 80). Those remaining 9 patients undergoing tumor progression were older, had larger tumors, and had a shorter follow-up at the time of tumor progression; the differences, however, were statistically not significant (data not shown). The pattern of treatment response was similar in both groups (data not shown).
Treatment Response
The “BEST” treatment response was usually achieved after 14 months (median). Complete response was seen in 18 patients, partial response in 33 patients, tumor control in 146 patients, and unrestrained tumor growth in 42 patients (nonresponder group). Patients with complete to partial response did significantly better than those showing tumor control (i.e., 5-year survival rates were 86% for the former group and 62% for the latter one; 10-year survival rates were 58% for the former group and 38% for the latter [P = 0.0004]). Patients with complete to partial response and tumor control did not differ in terms of age, KPS, tumor volume, the frequency of tumor enhancement, and applied tumor dose (P > 0.05). Patients of the nonresponder group were older and showed larger tumor volumes (P < 0.05); length of survival (5 yrs, 2%, 10 yrs, 0%) was significantly shorter (P = 0.0001).
Malignant Transformation
Malignant transformation afflicted 109 patients. The 5-, 10-, and 15-year malignant transformation rates were 33%, 54%, and 67%, respectively, and, once again, no plateau of the curve could be observed; 1 patient experienced malignant transformation even after more than 15 years (Fig. 3). Median age at the time of malignant transformation was 42.5 years (range, 20–75 yrs).
Rate of malignant transformation in 239 patients with WHO Grade 2 astrocytoma–oligoastrocytoma.
Prognostic Factors, Univariate Analysis
Predictors of survival are summarized in Table 2, and an almost identical prognostic pattern could be detected for progression-free survival (data not shown). The covariates CT enhancement, paresis or epilepsy, tumor location, and midline shift were correlated with the KPS (P < 0.01). Midline shift was significantly associated with tumor volume (P < 0.01). Risk factors for malignant transformation were 1) age > 35 yrs, 2) tumor enhancement, and 3) tumor volume > 20 mL. A shorter postrecurrence survival was associated with higher age at the time of presentation and/or malignant transformation at the time of tumor recurrence or tumor progression.
Prognostic Factors, Multivariate Model
A compilation of the “BEST” prognostic models for survival, progression-free survival, postrecurrence survival, and time to malignant transformation is shown in Table 4.
| Covariate | Survival | Progression | Malignant | Postrecurrence |
|---|---|---|---|---|
| Age > 50 yrs | ||||
| P | 0.009 | 0.009 | 0.05a | 0.0001 |
| RR | 1.7 | 1.6 | 1.5a | 1.8 |
| 95% CI | 1.1–2.5 | 1.1–2.3 | 1.0–2.2a | 1.3–2.5 |
| Karnofsky score | ||||
| P | 0.001 | 0.01 | — | — |
| RR | 1.8 | 1.4 | — | — |
| 95% CI | 1.3–2.6 | 1.1–1.9 | — | — |
| CT characteristics | ||||
| P | 0.03 | — | — | |
| RR | 1.6 | — | — | |
| 95% CI | 1.0–2.5 | — | — | |
| Tumor volume | ||||
| P | 0.005 | 0.0002 | 0.01 | — |
| RR | 1.5 | 1.7 | 1.6 | — |
| 95% CI | 1.2–2.3 | 1.3–2.3 | 1.1–2.4 | — |
| Malignant transformation | ||||
| P | — | — | — | 0.0005 |
| RR | — | — | — | 1.8 |
| 95% CI | — | — | — | 1.3–2.6 |
- RR: relative risk; CI: confidence interval.
- a Age > 35 yrs.
Survival/progression-free survival
In the “BEST” model for survival, age >50 years, a KPS <90, tumor volume > 20 mL, and CT-enhancement remained statistically important (Table 4). Nearly identical results could be calculated for progression-free survival. The adjusted 5-year survival rates for patients with 0, 1, 2, 3, or 4 unfavorable prognostic factors were in the range of 72%, 56%, 40%, and 26%, respectively. The adjusted 10-year survival rates for patients with 0, 1, 2, 3, or 4 unfavorable prognostic factors were in the range of 55%, 34%, 10%, 5.8%, respectively (Fig. 4). These prognostically different classes comprised 75, 92, 48, and 25 patients, respectively. The adjusted 5-year progression-free survival rates for patients with 0, 1, 2, or 3 risk factors were in the range of 50%, 35%, 18%, and 6%, respectively. The adjusted 10-year progression-free survival rates for patients with 0, 1, 2, or 3 risk factors were in the range of 31%, 17%, 6%, and 1%, respectively.
Estimated influence of different patterns of prognostic factors on survival rates for 239 patients with WHO Grade 2 astrocytoma–oligoastrocytoma as obtained from the Cox model. The baseline plot represents patients ≤ 50 years of age with a Karnofsky performance score ≥ 90, a tumor volume ≤ 20 mL, and no tumor enhancement. The strong impact of pretreatment factors is demonstrated.
Malignant transformation
Risk factors for malignant transformation were tumor volume > 20 mL and age. Adjusted Kaplan–Meier curves for risk of malignant transformation are shown in Figure 5.
Adjusted Kaplan–Meyer curves for malignant transformation showing the estimated influence of different patterns of prognostic factors. The baseline plot represents patients aged ≤ 35 years and a tumor volume ≤ 20 mL.
Post-recurrence survival
The “BEST” model contained malignant transformation and/or age at the time of presentation as significant risk factors. Median postrecurrence survival in patients with malignant transformation was 12% and without malignant transformation was 31% (P < 0.001, Fig. 2).
Radiogenic Complications
In 27 of 239 patients, radiogenic complications occurred; 19 patients showed transient symptoms (16 patients with headache and 3 patients with a paresis), which could be stabilized with steroids within 4 weeks. Progressive clinical symptoms were seen in 8 patients (7 with headache and 1 with a paresis). A space-occupying radionecrosis developed in these patients making surgical decompression (7 patients) or long-lasting steroid application (1 patient; 6 mos) necessary. Seven patients with progressive signs and symptoms recovered completely. Median tumor diameter was 4.2 cm in patients with radiogenic complications and 3.4 cm in patients without complications. Median tumor volume was 37 mL in patients with radiogenic complications and 21 mL in patients without complications. The difference was statistically significant (P < 0.001, Wilcoxon-test). Radiogenic complications occurred typically (in 26 of 27 patients) within the first 2 years after implantation, and no long-term complications were seen. The risk of interstitial radiosurgery was not influenced by tumor location, reimplantation, and/or in addition to performed external-beam irradiation.
DISCUSSION
The management of patients with supratentorial low-grade astrocytoma and oligoastrocytoma remains a controversially discussed challenge, and the prognostic impact of any applied treatment is difficult to assess. This has been recently highlighted by results of 3 prospective randomized studies.1-3 Neither early external-beam radiation (after tumor resection or stereotactic biopsy) nor tumor dose escalation (e.g., from 45 Gy to 59.4 Gy) resulted in better survival rates. However, patients treated with a higher tumor dose (in the range of 60 Gy) experienced more side effects of therapy.20 Whether these somehow disappointing results reflect the well known clinical and biologic heterogeneity of this tumor entity (confounding beneficial treatment effects of external-beam radiation for not yet identified subpopulations) or the predominant role of treatment independent factors remains unclear. Unfortunately, proposals for comparisons of conservative management (wait-and-see attitude after stereotactic biopsy) and more aggressive treatment strategies have not been realized.21 The aim of the current updated retrospective study was twofold, 1) to detail the long-term behavior of adult patients with supratentorial, circumscribed de novo astrocytoma or oligoastrocytoma who have a documented progression of their disease at the time of presentation and undergo interstitial radiosurgery as primary treatment and 2) to bring benefit and risk of this treatment strategy into the perspective of the overall prognosis of the disease. It remains to be shown to what extent the current analyses are also valid for patients with noncircumscribed (diffuse) astrocytoma or for those without progressive clinical signs and symptoms.
Rationale for Interstitial Radiosurgical Treatment
The aim of highly localized therapies, such as interstitial radiosurgery, is to devitalize a well defined treatment volume and to avoid damage of the surrounding tissue. The 125I-implant approach enables accurate application of high intratumoral doses, a rapid dose decrease toward the periphery, and extremely favorable biologically effective doses for late-responding tissue at the boundary of the target volume because of continuously applied low-dose rate radiation (for detailed information see Reference 16). These characteristics predestine interstitial 125I radiosurgery for minimally invasive treatment of circumscribed low-grade gliomas, which are diffuse infiltrating tumors harboring an interface of neoplastic and nonneoplastic cells particularly at the boundary of the target volume. The current data indirectly demonstrates favorable radiobiologic effects of an implanted 125I source on extralesional late-responding tissue: Neither a reimplantation (21 patients) nor additional external-beam radiation in case of tumor progression (109 patients) significantly increased risk of radiation injury. Thus, interstitial radiosurgery does not restrict treatment spectra for tumor recurrence or tumor progression.
Outcome
Five-year survival and 5-year progression-free survival after interstitial radiosurgery (and additional external-beam irradiation in case of tumor progression) were in line with all relevant retrospective and prospective data obtained within the CT era using various treatment strategies. Any study that reported better survival rates had included children, oligodendroglioma, WHO Grade 1 astrocytoma, predominantly lobar tumors, or had much shorter follow-up periods.1-3, 7-9, 22 The well known 5-year experience is now extended to more than 10 years; Ten-year overall survival and 10-year progression-free survival were 37% and 21%, and 15-year survival and 15-year progression-free survival rates were 26% and 14%, respectively. Laws et al., who have presented long-term results of a large and heterogeneously composed study group treated before the advent of CT (by various degrees of tumor resection and external-beam radiation), reported 10- and 15-year survival rates of 21% and 18%, respectively.23 A leveling off of survival curves beyond the 5-year time interval was noted, which suggested long-term stabilization, or even cure, from the tumor (after surgery and/or radiation therapy) for a significant number of patients. The conclusions drawn from the current long-term analysis of a much more homogeneous patient population treated in the CT era is less optimistic. Tumor progression, malignant transformation, and tumor-related death occurred even 15 years after treatment; a leveling off of the Kaplan–Meier curves was not observed for any of the chosen endpoints, and long-term tumor stabilization was rare (22 patients in this series). Powerful effects of lead time and length bias, inclusion of nonadult patients and those with oligodendroglioma, might have led to a considerable number of patients with long-term tumor stabilization in the study of Laws et al.23-25 A recently published report that has claimed real microsurgically related progress in survival of adult patients with low-grade glioma over time (1970–1981 vs. 1982–1993) should be regarded with extreme caution for similar reasons.8 There was no progress in length of survival over time in the current series: Patients treated in the latter phase of the project did not survive longer than those treated earlier (1979–1986), and date of treatment did not gain prognostic relevance in any of the created prognostic models.
Prognostic Factors for Survival and Progression-Free Survival
There is still no consensus on the relative importance of prognostic factors in WHO Grade 2 astrocytoma. Bauman et al., for example, by using recursive partitioning analysis of a multiinstitutional experience, identified higher age, poor clinical score, and focal enhancement of tumor in CT or MR imaging as unfavorable prognostic factors, which were associated with highly divergent survival rates.26 This conclusion, however, was biased by institution-related factors (which turned out to be a powerful prognostic factor). In addition, the prognostic influence of tumor volume was not tested, and the high frequency of patients with a KPS < 70 was remarkable (not typical for modern study populations suitable for surgical or radiosurgical treatment). Pignatti et al. reevaluated 2 Phase III multiinstitutional data sets of the European Organization for Research and Treatment of Cancer trials (Trial 22.844 for creation of the prognostic model and Trial 22.845 for validation) and identified increased age, large tumor size, tumors crossing the midline, preoperative neurologic deficits, and the histologic designation of astrocytoma as unfavorable predictors for length of survival. Information on intratumoral contrast enhancement was not available, and age was statistically important in the multivariate model but not in the univariate model for unknown reasons. The inclusion of infratentorial tumors, the high frequency of oligodendroglial tumors, and tumors crossing the midline (not typical for surgically or radiosurgically accessible tumors), highly different surgical treatment strategies (with regard to extent of resection), and a large number of incomplete data sets indicate limitations of the created model.27 The current analysis refers to a selected subpopulation with circumscribed, supratentorial tumors (diffuse lesions and those crossing the midline were not considered suitable for radiosurgery); the pretreatment clinical score was usually excellent; and the applied treatment concept was comparable for all patients. Age, KPS, tumor volume, and tumor enhancement divided the overall, and rather continuously, declining survival curve into divergent subsets with estimated 5- and 10-year survival rates ranging from as low as 7% and 0.8% to as high as 72% and 55%. Time to tumor progression was affected similarly powerfully by age, KPS, and tumor volume. The negative impact of increased age, however, concerned both time to tumor progression and length of postrecurrence survival and was, therefore, strongly related to length of survival. The prognostic impact of tumor size was not biased by treatment-related factors, as details of treatment parameters did not vary as a function of tumor size in this series. Oligoastrocytoma did not behave differently from astrocytoma. Whether a small group of patients with chemosensitive oligoastrocytoma may experience a more benign course of disease could not be elucidated.28 Women were older (median age, 39 vs. 34 yrs for men) in this series. This imbalance was related to worse prognosis for the elderly female subpopulation in our previously published intermediate analysis.5 However, the consideration of potential interactions between gender and age did not improve the fit of the prognostic models of the current long-term report.
In light of the described pronounced clinical (biologic) heterogeneity of this disease, identification and separate investigation of risk cohorts appears essential to detect treatment effects more clearly and to improve design of subsequent clinical trials.29 Modern treatment strategies will probably influence survival only if appropriate patient subgroups can be identified.
Malignant Transformation
Malignant transformation, which occurred even 15 years after treatment, was the most powerful negative predictor of postrecurrence survival and the major cause of death in this series. The event of malignant transformation must be considered the critical moment in the history of this complex disease: Once malignant transformation occurs, survival is short, and the clinical score decreases dramatically. This was indirectly expressed by the functionally independent survival curve, which follows the survival plot very narrowly. Patients > 35 years of age and/or those with a tumor volume > 20 mL experienced a significantly higher risk of malignant transformation in this series. Our finding supports preliminary data in the literature concerning an age-associated risk for malignant transformation.30 Other studies of our group have stressed the independent negative influence of TP53 mutations.31, 32 The impact of any applied therapy on risk of malignant transformation remains unclear. Whether early external-beam radiation could be beneficial for the older subpopulation (> 40 yrs) deserves further evaluation, and also the actual impact of aggressive cytoreductive surgery has to be elucidated.
Risk Estimation
It has been shown that risk of interstitial radiosurgery depends strongly on size of the lesion (for explanation see Reference 16), i.e., a steep increase in the frequency of radiogenic complications can be expected beyond a tumor diameter of 3.5 cm (tumor volume, 23 mL); The current data support these calculations with the median tumor volume in patients with radiogenic complications being significantly larger than in patients without complications (37 mL vs. 21 mL). Given the relatively large tumor volumes treated particularly at the beginning of this single-institution study, the reported frequency of side effects is not surprising: 76 (32%) patients had a tumor volume beyond the critical threshold of 23 mL. It could not be excluded that they would have rather been treated with microsurgery, a combination of microsurgery plus radiosurgery, or stereotactic RT.33, 34 Particularly the combination of 2 highly localized treatment strategies, such as microsurgery and radiosurgery, may be attractive for patients with large and eloquently located tumors and deserves further prospective evaluation.34 This combined approach could avoid the increased risk of suffering a neurologic deficit due to radical resection as well as the increased risk of radiogenic complications linked to interstitial radiosurgery of tumors with a diameter > 3.5 cm.
Radiogenic complications occurred typically within the first 2 years after treatment, were not influenced by tumor location, and, most importantly, long-term side effects were not observed. Exactly these characteristics and the possibility of performing a reimplantantion or a delayed external-beam radiation in case of tumor progression underline the minimally invasive character of interstitial radiosurgery.
Conclusions
Overall survival and progression-free survival of adult patients harboring circumscribed, supratentorial, WHO Grade 2 astrocytoma and oligoastrocytoma and a progression of their disease at the time of presentation is mainly determined by treatment-independent prognostic factors such as age, KPS, and tumor volume. Long-term stabilization of this disease is rare, and malignant transformation of the tumor is the major cause of death. Risk minimization must be considered the hallmark of any modern treatment strategy, and interstitial 125I radiosurgery fulfills this requirement for selected patients with circumscribed, supratentorial astrocytoma or oligoastrocytoma with a tumor diameter ≤ 3.5 cm. Long-term data analysis and risk assessment of comparable or alternative treatment strategies for well defined subpopulations are an indispensable prerequisite for development of individualized treatment concepts.
