Factors affecting risk of symptomatic temporal lobe necrosis: significance of fractional dose and treatment time

Int. J. Radiation Oncology Biol. Phys., Vol. 53, No. 1, pp. 75– 85, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/02/$–see front matter

PII S0360-3016(02)02711-6

CLINICAL INVESTIGATION

Brain

FACTORS AFFECTING RISK OF SYMPTOMATIC TEMPORAL LOBE NECROSIS: SIGNIFICANCE OF FRACTIONAL DOSE AND TREATMENT TIME ANNE W. M. LEE, F.R.C.R.,* DORA L. W. KWONG, F.R.C.R.,† SING-FAI LEUNG, F.R.C.R.,‡ STEWART Y. TUNG, F.R.C.R.,§ WAI-MAN SZE, F.R.C.R.,* JONATHAN S. T. SHAM, F.R.C.R.,† PETER M. L. TEO, F.R.C.R.,‡ TO-WAI LEUNG, F.R.C.R.,§ PO-MAN WU, PH.D.,† RICK CHAPPELL, PH.D.,㛳 LESTER J. PETERS, M.D.,¶ AND JOHN F. FOWLER, D.SC., PH.D.# Departments of Clinical Oncology, *Pamela Youde Nethersole Eastern Hospital, †Queen Mary Hospital, ‡Prince of Wales Hospital, and § Tuen Mun Hospital, Hong Kong, SAR, China; 㛳Department of Statistics, University of Wisconsin, Madison, WI; ¶Division of Radiation Oncology, Peter MacCallum Cancer Institute, Victoria, Australia; #Department of Human Oncology and Medical Physics, University of Wisconsin, Madison, WI Purpose: To study the factors affecting the risk of symptomatic temporal lobe necrosis after different fractionation schedules. Methods and Materials: One thousand thirty-two patients with T1-2 nasopharyngeal carcinoma treated with radical radiotherapy in Hong Kong during 1990 –1995 were studied. They were treated at four different centers with similar techniques but different fractionation schedules: 984 patients were given 1 fraction daily throughout (q.d.), and 48 patients were irradiated twice daily (b.i.d.) for part of the course. The median total dose was 62.5 Gy (range 50.4 –71.2), dose per fraction was 2.5 Gy (range 1.6 – 4.2), and overall treatment time (OTT) was 44 days (range 29 –70). In addition, 500 patients received supplementary doses for parapharyngeal extension, 113 received booster doses by brachytherapy, and 114 received sequential chemotherapy using cisplatin-based regimes. Results: Altogether, 24 patients developed symptomatic temporal lobe necrosis: 18 from the q.d. group and 6 from the b.i.d. group. The 5-year actuarial incidence ranged from 0% (after 66 Gy in 33 fractions within 44 days) to 14% (after 71.2 Gy in 40 fractions within 35 days). Multivariate analyses showed that the risk was significantly affected by the fractional effect of the product of total dose and dose per fraction (hazard ratio [HR] ⴝ 1.04, 95% confidence interval [CI] 1.02–1.05), OTT (HR 0.88, 95% CI 0.80 – 0.97), and b.i.d. scheduling (HR 13, 95% CI 3–54). Repeating the analyses for patients treated with the q.d. schedules confirmed the independent significance of OTT in addition to the product of total dose and dose per fraction. Conclusion: The tentative results suggest that in addition to fractional dose, the OTT also had significant impact on the risk of temporal lobe necrosis, and b.i.d. scheduling increased the hazard further. © 2002 Elsevier Science Inc. Nasopharyngeal carcinoma, Brain necrosis, Time, Dose, Fractionation.

INTRODUCTION

Up to the mid-1990s, the conventional technique designed by Ho (4) was used by all centers in Hong Kong. Because the target volume routinely included the whole sphenoid sinus, the inferomedial portions of temporal lobes were irradiated to a substantial dose (Figs. 1 and 2). Together with the unfortunate use of schedules with doses ⬎2 Gy per fraction (because of a serious shortage of treatment machines), the incidence of temporal lobe necrosis (TLN) was 3% (138 of 4527) for patients treated at the Queen Elizabeth Hospital during 1976 –1985 (5). There is little

Cerebral necrosis after radiotherapy (RT) of extracranial tumors was first reported by Fischer and Holfelder in 1930 (1). One of the most common tumors incriminated is nasopharyngeal carcinoma (NPC), despite the rarity of this cancer in Western countries (2, 3), because of the anatomic proximity of the temporal lobes and the need for adequate coverage of all potential sites of invasion for this highly infiltrative cancer.

Choy, Peter Choi, Philip Johnson, S. K. O, for their support, Dr. Y. L. Chan for the radiologic investigations at Prince of Wales Hospital, and the staff of the four participating centers for managing this series of patients. Received Jul 6, 2001, and in revised form Oct 29, 2001. Accepted for publication Oct 31, 2001.

Reprint requests to: Anne W. M. Lee, F.R.C.R., Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan, Hong Kong. Tel: 852-25-95-4173; Fax: 852-29-04-5216; E-mail: [email protected] Presented in part at the 6th International Congress of Radiation Oncology, Melbourne, 2001. Acknowledgments—The authors thank Drs. Gordon Au, Damon 75

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Fig. 1. Conventional technique designed by Ho for NPC: en-bloc lateral-opposed fields and 3-field arrangement.

doubt that fraction-size effect is one of the most significant factors (6). With the gradual improvement in resources, conventional fractionation with 2 Gy per fraction has been increasingly used, although progress varies among different centers because of differences in patient loads and historical practice. However, amid the general optimism of improvement, a sudden surge in the incidence of TLN was reported from the Prince of Wales Hospital (PWH) when accelerated fractionation (AF) schedules were tested (7–9). After 1.6 Gy per fraction, twice daily (b.i.d.), to a total of 67 Gy in 6 weeks, 35% (8 of 23) of patients developed classic radiologic signs of TLN, and one half became symptomatic within 3.5 years (7). This was unexpected because Wang of Massachusetts General Hospital (10) has used a similar scheme since 1979, and none of his 134 NPC patients had major neurologic complications. One likely explanation is the difference in technique. Although Dr. Wang also advocates routine coverage of the base of the skull, sphenoid sinuses, and cavernous sinuses during the initial phase, portals for boosting the dose to the primary site are coned down to avoid neurologic structures after 38.4 Gy. Despite attempts to minimize the irradiated volume of temporal lobes by additional shielding and to increase the interfraction interval to ⱖ6 h, an excessive incidence of neurologic damage was again observed in a subsequent study on AF from PWH (8, 9). Among 77 patients treated with 71.2 Gy in 40 fractions within 35 days, the total incidence of TLN amounted to 40% (29% asymptomatic and 12% symptomatic). These data are puzzling and disturbing. With increasing

evidence showing the efficacy of AF for other head-andneck cancers (11–14), it is important that this strategy also be explored for NPC. A better understanding of the repair kinetics and tolerance of the human brain is crucial. Hence, data from different centers in Hong Kong were pooled together to study the factors affecting TLN and its incidence after different schedules. METHODS AND MATERIALS Patient characteristics Four oncology centers in Hong Kong participated in this analysis: Tuen Mun Hospital, Queen Mary Hospital, PWH, and Pamela Youde Nethersole Eastern Hospital. The following inclusion criteria were set to ensure maximal number of long-term survivors, with minimal heterogeneity in the volume of temporal lobes irradiated, and reasonably long follow-up for assessing TLN: Period of analysis: Patients treated with radical RT during 1990 –1995. Histologic features: Undifferentiated or nonkeratinizing squamous cell carcinoma of the nasopharynx. T stage: Tumor confined to the nasopharynx or adjacent soft tissues (i.e, T1-2 by Ho’s system (15)), as staged by CT and/or MRI. M stage: No clinical evidence of distant metastasis at presentation. Primary treatment: A complete course of megavoltage RT using the en-bloc technique or the 3-field technique designed by Ho (4).

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Fig. 2. Computerized plan showing (A) isodose distribution at coronal plane and (B) dose–volume histogram of left temporal lobe from a patient treated with the en-bloc technique to 66 Gy by Scheme A (with cone-down at 60 Gy and no pituitary shield).

No coexisting malignancies, except basal cell carcinoma of the skin. Altogether, 1032 patients fulfilled these inclusion criteria. The age range was 17– 86 years (median 46), and the male/female ratio was 2:4:1. Of the 1032 patients, 995 (96%) had been regularly followed until death or the current assessment. The median duration of observation was 5.1 years (range 0.2–9.7). All survivors had a minimal follow-up of ⱖ4 years. RT technique All patients were treated with 4 – 6 MV photons from linear accelerators. The target volume included the primary tumor, all potential sites of local infiltration (parapharyngeal spaces, base of skull, sphenoid sinus, posterior parts of nasal fossae, and maxillary and ethmoid sinuses), and bilateral cervical lymphatics. All were treated with conventional two-dimensional techniques (Fig. 1). The 3-field technique was used for 199 patients without oropharyngeal extension or high cervical lymphadenopathy. This consisted of lateral-opposed plus anterior facial fields for the nasopharyngeal region and an anterior cervical field for the whole neck. The remaining 833 patients were treated with the en-bloc technique that covered the primary tumor and enlarged neck nodes by lateral-opposed faciocervical fields to 40 Gy (or the equivalent) before changing to the 3-field technique. All treat-

ment was simulated and checked with verification films at the beginning of each phase. With either technique, the upper border of the nasopharyngeal fields was set at 5 mm above the roof of the sphenoid sinus. Computerized planning was not routinely performed during this period, and data on the three-dimensional dose distribution were mostly unavailable in this series. To illustrate the approximate volume and dose to the temporal lobes, the dosimetry distribution and dose–volume histogram of a patient treated by the en-bloc technique was reconstructed (Fig. 2). Shielding of the hypothalamic-pituitary and adjacent temporal lobe region was added in 377 patients: 354 throughout the whole course of RT and 23 after a median dose of 40 Gy (range 20 –50). A final cone down of facial fields to avoid the neurologic tissues was done in 114 patients after a median dose of 60 Gy.

Fractionation schedules The tumor dose was prescribed at the 100% isodose level, and the dose variation within the tumor target was ⫾5%. Table 1 lists the different fractionation schedules used by the different centers during different periods. For the 199 patients treated by the 3-field technique, the same dose per fraction (d) was used throughout the whole course (median 2.5 Gy, range 2– 4.2). All were treated with 1 fraction daily (q.d.) schedules. For those treated with the

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Table 1. Different fractionation schedules used during 1990 –1995 Scheme

Patients (n)

Fractionation schedule

D (Gy)

Dd (Gy2)

BED3 (Gy3)

Median OTT (d)

A B C D E F G H Others

141 126 89 53 218 108 212 48 37

2.0 Gy (5/wk) ⫻ 33 F 2.5 Gy (4/wk) ⫻ 24 F 2.5 Gy (5/wk) ⫻ 24 F 3.5 Gy (3/wk) ⫻ 17 F 2 Gy (5/wk) ⫻ 20 F ⫹ 2.5 Gy (4/wk) ⫻ 9 F 2 Gy (5/wk) ⫻ 20 F ⫹ 2.5 Gy (5/wk) ⫻ 9 F 2.5 Gy (4/wk) ⫻ 16 F ⫹ 3.5 Gy (3/wk) ⫻ 6 F 2.5 Gy (5/wk) ⫻ 8 F ⫹ 1.6 Gy (10*/wk) ⫻ 32 F Various

66 60 60 59.5 62.5 62.5 61 71.2 61.6†

132 150 150 208.3 136.3 136.3 173.5 131.9 146.2†

110 110 110 128.9 107.9 107.9 118.8 115.2 110.3†

45 (44–63) 42 (39–48) 34 (30–38) 42 (37–51) 45 (42–60) 39 (38–41) 48 (41–58) 35 (29–57) 40 (34–70)

Abbreviations: D ⫽ total dose; Dd ⫽ product of total dose and fractional dose; OTT ⫽ overall treatment time; /wk ⫽ fractions per week; F ⫽ fraction; BED3 ⫽ biological effective dose assuming ␣/␤ of 3 Gy ⫽ D [1 ⫹ (d/3)], with no correction for incomplete repair in Scheme H. Numbers in parentheses are the range of OTT. * Two fractions/d at 6-h interval. † Median value.

en-bloc technique, 725 patients were treated with q.d. schedules: the median d for Phase I was 2 Gy (range 2–2.5) and that for Phase II was 2.5 Gy (range 2– 4.2). The remaining 48 patients were treated with an AF schedule (Scheme H): 2.5 Gy q.d. for 8 fractions and then 1.6 Gy b.i.d. at 6-h interval for 32 fractions. For the whole series, the median total dose (D) was 62.5 Gy (full range 50.4 –71.2, 5%–95% 59.5– 66). The median for the parameter Dd (summation of the product of total dose and dose per fraction) was 136.3 Gy2 (full range 116.3–211.7, 5%–95% 131.9 –208.3). When converted to the biologic effective dose (BED) (16, 17) assuming an ␣/␤ ratio of 3 Gy (without any correction for incomplete repair in Scheme H), the median BED3 was 110 Gy3 (full range 91.3–128.9, 5%–95% 107.9 –128.9). The median overall treatment time (OTT) was 44 days (full range 29 –70, 5%–95% 33–50). The average dose given per week varied from ⱕ10 Gy in 507 patients, to ⬎10 but ⱕ12 Gy in 422 patients, and ⬎12 Gy in 103 patients. Ancillary treatment Supplementary treatment using a posterolateral field (below the base of the skull) was given to 500 patients with bulky parapharyngeal extension to minimize marginal misses. The median dose for this parapharyngeal boost was 10.5 Gy (range 7.5–14). An additional boost to the nasopharynx by brachytherapy was given to 113 patients with residual primary tumor 4 –12 weeks after completion of the basic course of RT. Using high-dose-rate iridium sources, the median dose prescribed at 1 cm from the mid-point of the plane of sources was 24 Gy (range 5– 40). Sequential chemotherapy using cisplatin-based regimens was given to 114 patients with extensive and/or bulky lymphatic involvement: 98 as induction and 10 as adjuvant therapy; 6 had both. None had chemotherapy concurrent with RT during this period.

Statistical analysis To minimize biases because of different investigation policies, the end point in the current study was the time to symptomatic TLN diagnosed by both classic clinical symptoms and radiologic features on CT and/or MRI (18, 19). Events were measured from the date of beginning RT. The actuarial rates of symptomatic TLN after different schedules were calculated with the Kaplan–Meier method (20) and the differences compared by the log–rank test (21). To avoid biases because of variation in the duration of follow-up, all statistical analyses were based on actuarial rates. However, as most publications only gave the crude rates, these are also shown to give a more comprehensive clinical picture. To assess the effect due entirely to the primary course of RT, events were censored at the time of repeated RT for the 95 patients who had a second course of RT for local recurrence. Deaths from any cause were also censored if they occurred before the diagnosis of symptomatic TLN. Univariate analyses were performed on the following variables: host factors (age, gender), volume factors (radiation technique, pituitary shielding, final cone-down), primary radiation factors (D, Dd, OTT, b.i.d. scheduling), ancillary treatment (parapharyngeal boost, brachytherapy boost, chemotherapy), and occult factor in treatment/detection (oncology center). Significant factors identified were then tested further with multivariate analyses using the Cox proportional hazards model (22) to assess their independent effect. All the statistical tests were performed using Microsoft Access and Statistical Package for Social Systems, version 7.

RESULTS Radiologic changes suggestive of TLN were detected in 51 patients after primary RT for NPC (Table 2). The total crude incidence ranged from 33% after Scheme H and 25% after Scheme D to 0% after Scheme A. However, part of the

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Table 2. Total incidence of TLN detected after different schemes Crude incidence (%) of TLN

Scheme

Median follow-up (y)

Progress scans* (%)

Asymptomatic

Mild

Severe

A (n ⫽ 141) B (n ⫽ 126) C (n ⫽ 89) D (n ⫽ 53) E (n ⫽ 218) F (n ⫽ 109) G (n ⫽ 212) H (n ⫽ 48) Others (n ⫽ 37) All (n ⫽ 1032)

4.1 6.7 5.1 6.9 6.1 4.1 6.2 4.9 4.5 5.1

28 25 38 28 11 8 9 88 8 22

0 (0) 3 (2.4) 8 (9.0) 4 (7.5) 0 (0) 0 (0) 2 (0.9) 10 (20.8) 0 (0) 27 (2.6)

0 (0) 1 (0.8) 2 (2.2) 5 (9.4) 1 (0.5) 1 (0.9) 1 (0.5) 2 (4.2) 0 (0) 13 (1.3)

0 (0) 0 (0) 0 (0) 4 (7.5) 2 (0.9) 0 (0) 1 (0.5) 4 (8.3) 0 (0) 11 (1.1)

Symptomatic

Abbreviation: TLN ⫽ temporal lobe necrosis. * Proportion of patients with at least 1 progress scan (CT and/or MRI) during follow-up period.

total crude incidence, the 5-year symptomatic TLN rate ranged from 14% with Scheme H and 8.1% with Scheme D to 0% with Scheme A. The crude incidence after the other schemes ranged from 0.8% (after Scheme B) to 2.3% (after Scheme C). The actuarial TLN rate incurred by Scheme C (1.4% at 5 years and 17.9% at 8 years) was significantly higher than that with Scheme B ( p ⫽ 0.02). Both schemes gave 2.5 Gy per fraction q.d. to a total of 60 Gy, the only difference was the shortening of the scheduled OTT from 39 days for Scheme B (4 fractions weekly) to 30 days for Scheme C (5 fractions weekly). The significant factors identified by univariate analyses are listed in Table 4. In addition to all the radiation factors (D [ p ⫽ 0.01], Dd [ p ⫽ 0.01], OTT [ p ⬍ 0.01], and b.i.d. [ p ⬍ 0.01]), other significant factors included T stage (T2 vs. T1, 1.5% vs. 4.3% p ⫽ 0.02), parapharyngeal boost (yes vs. no, 1.2% vs. 3.4%, p ⫽ 0.04), and oncology center ( p ⫽ 0.01). When these factors were tested further with multivariate analyses, D ( p ⫽ 0.65), T stage ( p ⫽ 0.24), parapharyn-

difference could have been due to detection biases, because the proportion of patients with progression scan by CT/MRI during follow-up varied from 88% (Scheme H) to 8% (Scheme F). Hence, all the following analyses were based on the 24 patients (2.3% of the whole series) who developed classic symptoms in addition to radiologic signs of TLN. Of the 24 patients, 13 had only mild symptoms (mild memory impairment, personality change, and/or dizziness), and 11 were seriously affected (marked debilitation, pressure symptoms, epileptic attacks, and/or changes in conscious level); 3 (0.3% of the whole series) died of this complication. The incidence of severe debility (Table 2) was again highest after Scheme H (8.3%) and Scheme D (7.5%). The median latency for the manifestation of symptomatic TLN for the whole series was 4.1 years (range 1.9 – 8.3). The minimal latency varied from 2 years after Schemes D and H to 8 years after Scheme B (Table 3). The overall difference in the actuarial TLN rates after different schedules (Fig. 3 and Table 3) was strongly significant ( p ⬍ 0.01). Similar to the trend observed with the

Table 3. Symptomatic temporal lobe necrosis detected after different schemes Actuarial rate (%) Scheme

Latency minimum (y)

Crude no. (%)

5-y

8-y

p*

A (n ⫽ 141) B (n ⫽ 126) C (n ⫽ 89) D (n ⫽ 53) E (n ⫽ 218) F (n ⫽ 109) G (n ⫽ 212) H (n ⫽ 48) Others (n ⫽ 37) All (n ⫽ 1032)

— 8.3 3.3 1.9 4.1 2.8 2.8 2.2 — 1.9

0 (0) 1 (0.8) 2 (2.3) 9 (17.0) 3 (1.4) 1 (0.9) 2 (0.9) 6 (12.5) 0 (0) 24 (2.3)

0 0 1.4 8.1 1.5 1.4 0.6 14.0 0 2.0

— 0 17.9 24.9 2.6 — 1.8 — 0 5.2

— — 0.21 0.01 0.44 0.22 0.42 ⬍0.01 —

* Comparison with Scheme A by log–rank test.

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Fig. 3. Symptomatic temporal lobe necrosis: actuarial rates after different fractionation schedules.

geal boost ( p ⫽ 0.26), and oncology center ( p ⫽ 0.74) failed to reach statistical significance. The factors that remained independently significant and their respective impact in terms of hazard ratio (HR) and corresponding 95% confidence interval (CI) are listed in Table 5. The HR for Dd was 1.04/Gy2 (95% CI 1.02–1.05), for OTT was 0.88/d (95% CI 0.80 – 0.97), and for b.i.d. was 13 (95% CI 3–54). When D and Dd were replaced with BED3, the impact of OTT remained almost the same (HR 0.87, 95% CI 0.79– 0.96); b.i.d. also remained significant, but the effect decreased (HR 4, 95% CI 1.06 –14), and BED3 showed independent significance with a HR of 1.13/Gy3 (95% CI 1.07–1.19). Repeating the multivariate analyses in the 984 patients treated with q.d. schedules (Table 4) confirmed the significant impact of OTT together with Dd or BED3. DISCUSSION With the anatomic proximity of the temporal lobes, TLN is one of the most serious late complications after radical RT for NPC (5, 18). Table 6 summarizes the incidence of positive events after primary RT for NPC reported in English literature (5, 7–9, 23–28). A cross series comparison is invalid because of the marked differences in the proportion of long-term survivors receiving regular follow-up, duration of observation, index

of suspicion, and diligence of the investigations among different series. Because the median latency is ⱖ4 years (5 in the current study), series without substantial numbers of long-term survivors will grossly underestimate the problem. This is probably one major reason why AF schedules have not been reported as unduly toxic in the treatment of primary brain tumors (29). Furthermore, because more than one half of patients with TLN in the current study and the study of Lee et al. (18) had no or minimal symptoms, the problem can be easily missed by the unwary. Nevertheless, the incidence of TLN observed in the past series from Hong Kong raised serious concerns. The crude incidence from overseas centers was ⱕ1.4% (23–27), whereas that at the Queen Elizabeth Hospital during 1976 – 1985 (5) and Queen Mary Hospital during 1988 –1991 (28) were both 3%. More worrisome still is the high incidences at PWH—amounting to 9.8% (4 of 41) during 1986 –1988 (7) and 7.5% (12 of 159) during 1993–1995 (9), even if the end point was confined to symptomatic TLN only. At least part of the variation in the TLN rate between the local and overseas centers could be attributed to differences in RT technique and/or fractionation. Most overseas series tend to have smaller volumes of temporal lobes irradiated, because narrower margins (especially in the cranial direction) are generally used (10, 30, 31), and field reduction for

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Table 4. Univariate analyses of possible factors for symptomatic temporal lobe necrosis Factor Host factor Age (y) Gender (male vs. female) Tumor factor T stage (T2 vs. T1) Volume factor Technique (en-bloc vs. 3-field) Pituitary shield (yes vs. no) Final cone-down (yes vs. no) Ancillary treatment Parapharyngeal boost (yes vs. no) Brachytherapy boost (yes vs. no) Chemotherapy (yes vs. no) Radiation factors D (Gy) Dd (Gy2) OTT (d) b.i.d. (yes vs. no) Occult factor Oncology center

Hazard ratio

95% CI

p 0.92 0.93

0.40

0.18–0.89

0.02 0.13 0.39 0.22

0.39

0.15–0.97

0.04 0.64 0.14

1.18 1.02 0.85 12

1.04–1.33 1.01–1.04 0.79–0.92 4–32

0.01 0.01 ⬍0.01 ⬍0.01 0.01

Abbreviations: CI ⫽ confidence interval; D ⫽ total dose; Dd ⫽ product of total dose and fractional dose; OTT ⫽ overall treatment time; b.i.d. ⫽ schedule with 2 fractions daily.

the final phase is advocated. Furthermore, conventional fractionation with d ⱕ2 Gy is mostly used (24, 25, 27). The data from Hong Kong provide an interesting opportunity to study the fractionation effect, because all oncology centers used the same basic techniques (4) but different fractionation schedules up to the mid-1990s. To minimize the heterogeneity in volume, the current study was confined to patients with T1-2 tumors. Although minor differences were present in the details of field

arrangements, pituitary shielding, and final cone-down, none of these had a significant impact in this selected series (Table 4). The only major variation (other than fractionation) among the different centers was the policy of radiologic investigations during subsequent follow-up (Table 2). Patients accrued to the AF study at PWH underwent MRI 2 years after RT completion (9), whereas the rest were investigated only when symptoms/signs of neurologic damage or

Table 5. Significant factors for symptomatic temporal lobe necrosis on multivariate analyses Factor All patients (n ⫽ 1032) Analyses of 7 variables* Dd (Gy2) OTT (d) b.i.d. (yes vs. no) Analyses of 3 variables† BED3 (Gy3) OTT (d) b.i.d. (yes vs. no) Patients treated with 1-fraction-daily schedules (n ⫽ 984) Analyses of 6 variables‡ Dd (Gy2) OTT (d) Analyses of 2 variables§ BED3 (Gy3) OTT (d)

Hazard ratio

95% CI

p

1.04 0.88 13

1.02–1.05 0.80–0.97 3–54

⬍0.01 0.01 ⬍0.01

1.13 0.87 4

1.07–1.19 0.79–0.96 1.06–14

⬍0.01 ⬍0.01 0.04

1.04 0.86

1.02–1.05 0.77–0.95

⬍0.01 ⬍0.01

1.13 0.85

1.07–1.19 0.76–0.94

⬍0.01 ⬍0.01

Abbreviations: CI ⫽ confidence interval; D ⫽ total dose; Dd ⫽ product of total dose and fractional dose; OTT ⫽ overall treatment time; b.i.d. ⫽ schedule with 2 fractions daily; BED3 ⫽ biological effective dose assuming ␣/␤ of 3 Gy. * Variables D, Dd, OTT, b.i.d., parapharyngeal boost, T stage, and oncology center † Variables BED3, OTT, and b.i.d. ‡ Variables D, Dd, OTT, parapharyngeal boost, T stage, and oncology center. § Variables BED3 and OTT.

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Table 6. Reports of TLN after primary RT for NPC in English literature Authors

Period

D (Gy)

d (Gy)

Bohorquez (23) Chatani et al. (24) Sanguineti et al. (25) Van Andel et al. (26) Perez et al. (27) Lee et al. (5) Sham et al. (28) Leung et al. (7)

1933–1956 1978–1980 1954–1992 1966–1980 1956–1986 1976–1985 1988–1991 1986–1988

Teo et al. (9)

1993–1995

⬍50–70 ⬍50–84 58–76 40–68 55–70 ⬍50–66 59.5–61 60 67.2 60 71.2

NR 2 q.d. 1.5*–2 (92% q.d.) 2–2.3 q.d. 1.8–2 q.d. 2–4.2 q.d. 2.5–3.5 q.d. 2.3–2.5 q.d. 1.6 b.i.d. 2.5 q.d. 2.5 q.d. ⫹ 1.6 b.i.d.

OTT (wk)

Crude incidence (%)

NR 5–9.4 6.9† 4–6 5.5–7.8 6 6 6 6 5.2 5.1

1/152 (0.7) 1/105 (1.0) 4/378 (1.1) 1/86 (1.2) 2/143 (1.4) 138/4527 (3.0) 5/152 (3.3) 1/18 (5.6) 8/23 (34.8) 16/82 (19.5) 31/77 (40.3)

Abbreviations: TLN ⫽ temporal lobe necrosis; RT ⫽ radiotherapy; NPC ⫽ nasopharyngeal carcinoma; D ⫽ total dose; d ⫽ dose per fraction; OTT ⫽ overall treatment time; NR ⫽ not reported; q.d. ⫽ 1 fraction daily; b.i.d. ⫽ 2 fractions daily. * Fractional dose for concomitant boost in 8% of the series. † Median value.

tumor recurrence developed. Hence, the defining event for the current study was confined to symptomatic TLN instead of the total incidence. Although greater alertness might still lead to detection biases, the effect is likely to be small, because the oncology center per se was statistically insignificant in the multivariate analyses (Table 5). Fractionation is obviously a major factor affecting actuarial TLN rates (Fig. 3 and Table 3). None of the 141 patients treated by conventional fractionation of 2 Gy 5 times weekly (Scheme A 66 Gy in 33 fractions within 44 days) developed TLN up to a median follow-up of 4.1 years. Although those treated by Scheme D (59.5 Gy in 17 fractions within 37 days) and Scheme H (71.2 Gy in 40 fractions within 36 days) showed significantly more serious damage, reflected not only by the overall TLN rate, but also by the proportion with severe debility and shortest latency (Tables 2 and 3). There is little doubt that d ⬎2 Gy incurs greater damage to the temporal lobes. With d at 3.5 Gy, the high actuarial TLN rate after Scheme D (8% at 5 years) can be readily explained by its high BED3 of 128.9 Gy3, equivalent to 77.3 in 2-Gy fractions (by the linear quadratic equation assuming ␣/␤ ratio ⫽ 3 Gy for late effect). Multivariate analyses in the current study (Table 5) concur with our previous finding (6) that the parameter Dd (HR 1.04, 95% CI 1.02–1.05, p ⬍ 0.01) was even more important than D alone ( p ⫽ 0.65). However, the differential protection gained by using d ⬍2 Gy remains uncertain. With d at 1.6 Gy for 32 of 40 fractions, the high actuarial TLN rate after Scheme H (14% at 5 years) cannot be explained by its BED3 of 115.2 Gy3, without additional correction for incomplete repair. Multivariate analyses showed that b.i.d. scheduling was a significant factor independent of other radiation factors (Table 5); the hazard of symptomatic TLN was ⱖ4-fold that of q.d. schedules ( p ⱕ 0.04). In addition, OTT was a strongly significant factor independent of Dd and b.i.d. (Table 5): the hazard of symptomatic TLN decreased by a factor of 12% for each day of prolongation (95% CI 3–20%, p ⫽ 0.01). A similar magnitude of impact was consistently shown when D and Dd

were replaced with BED3, and when the analyses were repeated with the rate from the 984 patients treated by q.d. schedules. A comparison of two q.d. schedules with the same D (60 Gy) and d (2.5 Gy) revealed that shortening the OTT from 39 to 30 days incurred a significantly higher TLN incidence (crude rate 2.3% vs. 0.8%, 5-year actuarial rate 1.4% vs. 0%, p ⫽ 0.02). This finding of the significance and the magnitude of impact of OTT were rather unexpected because the classic teaching is that the time factor is unimportant for latereacting tissues, particularly nervous tissues that have little capacity for repopulation (32, 33). Confirmation of this finding is clinically important, because the strategy of AF is built on the radiobiologic concept that the time factor affects tumor and acute tissues, but not late-reacting tissues. Accurate knowledge of the maximal safe limit is vital. A review of the literature revealed interesting conflicts. Although data are abundant on the effect of OTT for tumor control, very few studies have shown any attempt to analyze this factor for late complications. Data suggesting an independent effect were first reported in the 1970s by Wara et al. (34) and Field et al. (35, 36). Both groups found an independent (although relatively small) exponent from OTT for radiationinduced pneumonitis in mouse lungs. Field and coworkers also showed that an increase of 0.1 Gy/d was needed to produce the same level of pneumonitis (35) and suggested that this phenomenon might be due to a process of “slow repair” (36). White and Hornsey (37) also reported a time-dependent repair in rat lumbar spinal cord in 1980 and suggested that the slow phase of repair could be attributed to the proliferation of neurologic cells (38). However, these findings were not supported by other animal experiments (39– 41). Of the few clinical studies that had analyzed this factor, more than one half reported no obvious time effect (6, 42– 45). However, only one of these studies had a subset treated by hyperfractionation to 74 Gy in 6 weeks (45), and none included markedly accelerated schedules. In particular, although the OTT in our previous study on TLN ranged from 38 to 75 days, the variation was ⱕ4 days among 85%

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Table 7. Reports of unexpected/excessive late toxicity after accelerated fractionation Authors

d (Gy)

F (n)

Hr (h)

Peracchia and Salti (49) Saunders et al. (50) Wong et al. (51) Leung et al. (7) Horiot et al. (12)

2 ⱕ1.5 1 1.6 1.6

3 3 4 2 3

4 6 3 4 4

⬍54/⬍2 ⬍54/⬍2 ⬍45/⬍3 67.2/6 vs. 60/6 72/5 vs. 70/7

Jackson et al. (52) Fu et al. (11)

2 ⬍1.8

2 2

6 6

66/3 vs. 66/7 72/6 vs. 70/7

2 1.6

1 2

24 6

Skladowski et al. (14) Teo et al. (9)

D (Gy)/OTT (wk)

⬍72/5 vs. ⬍72/7 71.2/5 vs. 60/5

Late complication Serious necrosis: 55% Myelitis: 4% (head-and-neck cancers) Myelitis: 6% TLN: 35% vs. 6% Severe functional damage: 14% vs. 4% CNS toxicity by AF: 4% Grade 4 toxicity: 24% vs. 6% Grade ⱖ3 toxicity: 37% vs. 27% Grade ⱖ4 toxicity: 8% vs. 8% Grade 4 toxicity: 22% vs. 0% CNS toxicity: 49% vs. 23%

Abbreviations: d ⫽ dose per fraction; F ⫽ fraction; Hr ⫽ interfraction interval; D ⫽ total dose; OTT ⫽ overall treatment time; TLN ⫽ temporal lobe necrosis; CNS ⫽ various neurologic structures; AF ⫽ accelerated fractionation.

of the series (6). It is therefore possible that the failure to reach statistical significance was due to the narrow range of this parameter. The first clinical study revealing a significant influence of OTT on late effect was reported by Maciejewski et al. in 1990 (46). Based on the data from 498 patients with cancer of the oral cavity and oropharynx (most treated with d ⬎2 Gy), their estimation showed that an increase of 0.3 Gy (95% CI 0.2– 0.3) was needed to produce the same level of late injury for each day of prolongation beyond 21 days (p ⫽ 0.01). Interestingly, the authors concluded that this “unexpected” correlation was perhaps just a secondary consequence of variations in the severity of acute responses and that a similar effect would not be expected for all late-responding tissues. The study by Withers et al. (47) on various schedules from 9 different institutions supported this suggestion: the hazard of late mucosal ulceration decreased by a factor of 65% per 10-day period (p ⬍ 0.01), but the impact on bone and muscle were statistically insignificant ( p ⬎ 0.5). On the other hand, the analyses by Chappell et al. (48) of patients from two trials with OTT varying from 3 to 7 weeks by the British Institute of Radiology showed a significant 2% reduction in the probability of late injuries (all normal tissues included) per day of increase in OTT ( p ⬍ 0.01). Again, the authors found this rate unexpectedly large and doubted the reliability of their finding. Because the time factor became insignificant when the end point was confined to telangiectasia of mucous membrane alone ( p ⫽ 0.2), the usefulness of the “all normal tissues” generalization was commented as being questionable. In addition to the expected increase in acute toxicity, evidence is increasing of unexpected/excessive late morbidity after various AF schedules (7, 9, 12, 14, 49 –52) (Table 7). The normal structures damaged are not limited to those that manifest both acute and late responses to irradiation. Neurologic structures (brain, spinal cord, cranial nerves), the most classic late-reacting tissues, are not exempted (7–9, 12, 50, 51). Since the report of 4 cases of radiation myelitis after continuous hyperfractionated accelerated RT in 1991 (50), 2 additional cases have been reported from the European Organization for Research and Treatment of Cancer 22851 Trial (12), and 2 from the Princess Margaret Hospital

in Toronto (51), with cord doses of ⱕ48 Gy (range 40 – 48). Hence, damage consequential to severe acute reaction is probably not the only cause of excessive late toxicity. One possible important attribute is incomplete repair of sublethal injury. A study on the rodent spinal cord by Ang et al. (53) suggested a bi-exponential model, with repair half-times of 0.7 and 3.8 h in 37% and 62% of injuries, respectively. Even longer half-times (⬎5.5 h) for the slow component was suggested by another animal experiment (54). Extensive review of human data by Thames et al. (55) suggested that recovery might be slower in humans than in rodents. After a review of various head-and-neck trials, Bentzen et al. (56) demonstrated that the half-time for human mucosal damage was about 2– 4 h and that for laryngeal edema, skin telangiectasia, and subcutaneous fibrosis was ⱖ4 h (57). Different mathematical models have been proposed to reflect incomplete repair. The excess in TLN rate after the b.i.d. schedule in the current report could best be explained by the reciprocal repair model (58), which estimated that the BED3 for Scheme H was as high as 139.9 Gy3. However, even this could not adequately explain the significance of OTT in most patients who were treated with q.d. schedules. It is likely that other recovery processes exist. Possibilities include repopulation of glial cell precursors (59), as previously suggested by Hornsey and coworkers (37, 38), and secondary changes due to repopulation of the supporting vasculature (60). These mechanisms are not mutually exclusive. A review of the schedules with unexpected/excessive late toxicity (Table 7) revealed at least one of the following features: ⱖ3 fractions daily, ⱖ3.2 Gy/d, and/or ⱖ14 Gy/w. Early results from other series with moderate acceleration have demonstrated the encouraging possibility of improving tumor control without excessive late toxicity. With a concomitant boost of 1.8 Gy given ⱖ6 h after large field irradiation of 1.5 Gy for the last 12 treatment days (11), the Grade 4 toxicity rate was the same as that by conventional fractionation (8% vs. 8%), although Grade ⱖ3 toxicity by Radiation Therapy Oncology Group criteria did increase significantly (37% vs. 27%). The trial on 7-day continuous accelerated irradiation showed that excessive Grade 4 tox-

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● Biology ● Physics

icity could be successfully avoided (22% vs. 0%) by reducing the weekly dose from 14 to 12.6 Gy (14). The Danish Head-and-Neck Cancers (DAHANCA) 6 and 7 trials on head-and-neck cancers also showed that moderate acceleration by 2 Gy per fraction, 6 fractions weekly to a total of 66 – 68 Gy could achieve significant improvement in tumor control with no significant differences in late complications (13). The current study, together with supporting evidence from the literature, suggest that both OTT and b.i.d. scheduling, in addition to fractional effect, have an important impact on late damage (at least in the temporal lobes). The results are still tentative because of the small number of TLN events and relatively short follow-up. However, the consequence of damage is such a serious concern that it is prudent to avoid excessive acceleration and maintain a 24-hour interfraction interval (as far as possible), unless the RT technique can be refined to protect normal structures adequately without risking marginal misses. Among the various AF schedules, the DAHANCA 7 schedule is the most attractive because this theoretically incurs the lower risk of excessive late damage and has less demand for extra resoures. Because the machine use per patient remains the same, it is more easily affordable in

Volume 53, Number 1, 2002

Asian countries in which a shortage of treatment machines is a common problem. A pilot study on NPC using 2 Gy per daily fraction, 6 fractions weekly (Monday to Saturday) to a total of 66 Gy, has reported promising early results (61). Using the same two-dimensional technique as in the current study, the AF group showed significant improvement in the 3-year progression-free survival rate (74% vs. 63%, p ⫽ 0.02) without an excessive increase in late toxicity Grade ⱖ3 (20% vs. 15%, p ⫽ 0.19) compared with historical controls treated with the conventional 5 fractions weekly. Furthermore, none of the 158 patients (median follow-up 2.4 years) developed TLN after a single course (61). A multicenter prospective randomized trial is currently being conducted, not only to confirm the therapeutic gain by this moderate AF, but also to study the relative value of concurrent chemotherapy and the possibility of combining the two new strategies to achieve additional benefits for locally advanced NPC. In addition to optimizing fractionation, the importance of the refinement of the RT technique for maximal protection of normal tissues cannot be overemphasized. The tumor targets should be accurately designed and the best possible conformal technique should be used to reduce the volume of critical structures irradiated.

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