Inl. J Radialion Oncology Bid Phys., Vol. 19, pp. 341-348 Printed in the U.S.A. All rights reserved.

Copyright

0360.3016/90 $3.00 + .OO 0 1990 Pergamon Press plc

??Original Contribution

TUMOR AND NORMAL TISSUE TOLERANCE FOR FRACTIONATED LOW-DOSE-RATE RADIOTHERAPY JOHN E. BOULDER, PH.D., Department

of Radiation

Oncology,

BRIAN L. FISH, B.S. AND J. FRANK WILSON, M.D.

Medical College of Wisconsin,

8700 W. Wisconsin

Ave., Milwaukee,

WI 53226

Radiobiological evidence

suggests that an improved therapeutic ratio might be achieved through the use of smaller than conventional dose fractions. The ultimate in small dose fractions for external beam radiotherapy would be fractionated low-dose-rate (LDR) irradiation, and clinical trials of fractionated external beam LDR therapy are already in progress. Using the BA1112 rat sarcoma, we have determined the 50% tumor control dose for LDR and for conventional-dose-rate (CDR) fractionated radiotherapy. These tumor control doses were compared to normal tissue tolerance doses for hemi-body irradiation in similar CDR and LDR schedules. Animals were treated 3 times per week without anesthesia using lo-19 fractions. LDR radiotherapy was done with 6oCo at dose rates of 0.0280.033 Gy/min; CDR radiotherapy was done with 250 kVp X rays at dose rates of 0.54-2.1 Gy/min. The tumor control dose modlification factor (DMF) for LDR compared to CDR irradiation was 1.3 (1.0-1.5). For LDR and CDR hemibody irradiation, the dose modification factor for 7 day lethality (gastrointestinal damage) was 1.7 (1.5 1.9), for 100 day morbidity was 1.8 (1.6-2.2), and for radiation nephritis at 90 days was 1.9 (1.7-2.3). The therapeutic gain factor for fractionated low-dose-rate irradiation compared to conventional-dose-rate fractionated radiotherapy was therefore 1.8j1.3 = 1.4 (1.2-1.8). The study shows that there is an experimental as well as a theoretical basis for anticipating a therapeutic benefit from the use of external beam fractionated LDR radiotherapy, and implies that the recognized therapeutic efficacy of brachytherapy is not due solely to the high localized dose. Radiotherapy,

Lalw-dose-rate, Normal tissue tolerance, Tumor control.

In 197 1 Pierquin (27) suggested that the advantages of implant radiotherapy could be extended to other sites through the use of fractionated LDR teletherapy. A clinical trial of fractionated LDR radiotherapy (0.0 15-0.022 Gy/min, 6-9 Gy per fraction, 5 days per week) in advanced head and neck cancer showed higher local control rates in the LDR arm, although it was achieved at the cost of a higher complication rate (28-30). The clinical trial is promising but leaves many questions unanswered. Is there an experimental basis for anticipating a therapeutic advantage for fractionated LDR therapy? What is the biological basis of the improved local control rates? How low does the dose rate have to be to achieve this improvement? Can this improvement be maintained in a combined treatment with low and conventional dose rates? Existing experimental LDR data are almost entirely based on single fraction data, and are not necessarily relevant to the above questions.

INTRODUCIION

Radiobiological evidence suggests that an improved therapeutic ratio might be achieved through the use of smaller than conventional dose fractions (6,36). This therapeutic advantage could be due to the differential accumulation or repair of sublethal radiation damage in tumors and normal tissues, or to a decrease in the oxygen enhancement ratio (OER) with l’ower doses per fraction. It can be argued that the ultimate in small dose fractions would be continuous low-dose-rate (LDR) irradiation, and LDR therapy has long been used in implant radiotherapy. While the efficacy of implant radiotherapy is unquestioned, it is not certain that this effic,acy is due solely to the lower dose rate. The efficacy of implants could also be due to the short overall treatment time, or to the high localized dose that is delivered with a rapid fall off outside the treatment volume (9, 10).

A preliminary version of this work was presented at the 28th Annual Meeting of the American Society of Therapeutic Radiology and Oncology, Los Angeles, CA, November 1986. Reprint requests to: John E. Moulder, Ph.D., Radiation Oncology, Medical College of Wisconsin, MCMC Box 165, 8700 W. Wisconsin Ave., Milwaukee, WI 53226.

This work was supported Grant CA24652. Accepted for publication

341

in part by National 22 February

1990.

Cancer lnstitute

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I. J. Radiation Oncology 0 Biology 0 Physics

With these issues in mind, we have designed an animal model system in which tumor control and normal tissue tolerance can be evaluated after fractionated LDR teletherapy. In this study we report results for a 3 fraction per week regimen delivered at 0.03 Gy/min (1.8 Gy/hr). METHODS

AND MATERIALS

Animals and tumors The study was done with defined, microbiologicallyassociated, female WAG/RijMCW rats bred in a moderate security barrier. These barrier-maintained rats are free of Mycoplasma pulmonis, Pseudomonas, and common rat viruses. Tumor animals remained in the barrier until irradiation; during and after irradiation they were housed in a conventional environment. No tumor animals died from intercurrent disease. Normal tissue animals were irradiated inside the barrier (conventional dose rate) or in a portable isolator (low dose rate), and remained in the barrier for the entire follow-up period. All animals used in these studies were 2 months old at the start of irradiation. The BAl 112 sarcoma is a nonimmunogenic (in the WAG/Rij rat), poorly differentiated, rhabdomyosarcoma with a volume doubling time of 2-2.5 days at the 6-7 mm diameter at which irradiations were begun (18, 19, 2 I,3 1). The hypoxic fraction of BA 1112 is 15-30% when measured by excision assays, and OS- 10% when measured by in situ assays (25). The procedure for maintaining the hosts (WAG/RijMCW rats) and the BA 1112 tumors were standard (18, 2 1). The tumor was grown subcutaneously on the lower back where it could be irradiated without anesthesia using lateral fields (18, 2 1). Irradiated animals were checked periodically for the presence of tumors and the recurrence date was defined as the interpolated date (measured from the start of treatment) on which the tumors reach a mean diameter of 15 mm; tumors were considered controlled if they had not recurred by 120 days (18,2 1). Fifty percent tumor control dose (TCDSo) values were calculated and compared by probit statistics and are shown with 95% confidence intervals (4). Dose modification factors (DMF) were calculated by direct comparison of the tumor control doseresponse curves and are shown with 95% confidence intervals (4).

Low dose-rate (LDR) irradiation For LDR tumor irradiations, unanesthetized rats were confined in acrylic plastic jigs (25) and irradiated, six at a time, with lateral beams of 6oCo -y-rays at a dose rate of 0.030 Gy/min and a source-to-surface distance (SSD) of 115 cm. The treatment field was defined by a lead block with six collimated 25 mm diameter holes; shielding was sufficient to reduce the dose to the animal to less than 5% of the tumor dose. Animals were irradiated 3 times per week, with a daily dose of 9.0 Gy (5 hr of treatment per day). Treatments were given from alternate sides on al-

August 1990. Volume 19, Number 2

ternate days. Each treatment was interrupted for 2-3 minutes after 1.5 and 3 hr to check animals and adjust tumor positioning. Any animals whose tumor was outof-position on more than 10% of the position checks was dropped from treatment; this rule resulted in the dropping of 3 out of 34 animals. The total tumor dose was varied by using different number of fractions; this is in contrast to the usual practice of holding the number of fractions constant and varying the dose per fraction. For LDR lower-hemibody irradiation, animals were confined in the same jigs used for tumor irradiations and were irradiated with a posterior-anterior 6oCo beam at a dose rate of 0.03 1 Gy/min and a SSD of 110 cm. The animals were shielded above the diaphragm with a lead block that was sufficient to reduce the upper-hemibody dose to 5% of the lower-hemibody dose. Animals were treated 3 times per week for lo- 18 fractions with doses per fraction of 3.7-7.2 Gylfraction. A 6 mm sheet of acrylic plastic was placed in the beam immediately before the animals to reduce the skin-sparing effect of the beam. Dosimetry was conducted with a Farmer-type ionization chamber in acrylic plastic phantoms. The dose reported are for the midline of the tumor or the abdomen. No relative biological effectiveness (RBE) corrections were made in the LDR 6oCo studies, so that the stated dose modification factors (DMF) include both a dose-rate component and an RBE component. Tumor doses in the LDR arm were confirmed with thermoluminescent dosimeters (TLD) that were attached to tumors during actual treatments; these measurements indicated that the dose fall-off across the tumor was less than 7%. For the lower hemi-body irradiations, the entrance and exit doses differed from the midline dose by 9%.

Conventional dose-rate (CDR) irradiation For CDR tumor irradiations, unanesthetized rats were confined in jigs identical to those used in the LDR studies and were irradiated with lateral beams of 250 kVp X rays with a half-value layer (HVL) of 0.5 cm Cu. Treatments were given from alternate sides on alternate days. Two treatment protocols were used. In the first protocol, animals were treated using the same jigs and collimator used in the LDR protocol, but at a dose rate of 0.54 Gy/min and an SSD of 82 cm. Animals were irradiated 3 times per week, with a daily dose of 6.2 or 9.7 Gy. As in the LDR protocol, the total tumor dose was varied by using different number of fractions. In the second protocol tumors were irradiated, as in previous studies (18, 2 I), at a dose rate of 1.25 Gy/min and an SSD of 55 cm; either 12 or 20 fractions were used, and the total dose was varied by using a range of doses per fraction. For CDR lower-hemibody irradiation, animals were confined to the same jigs and irradiated with lateral fields of 250 kVp X rays at a dose rate of 2.1 Gy/min, an HVL of 0.5 cm Cu, and an SSD of 40 cm. Treatments were given from alternate sides on alternate days. Dosimetry was conducted with a Farmer-type ioniza-

E. MOULDER et al.

Fractionated low-dose-rate radiotherapy 0 J. Table 1. Tumor Number

of

fractions 7” 105 15” 225 12 20 5-10 10-19 lo-16 * 50% + Slope t Ratio § Data

Dose per fraction (Gy) 6.7-14.9 4.7-10.4 5.1-10.0 4.3-6.9 5.8-8.3 4.0-6.0 9.7 6.25 9.0

control doses for fractionated

conventional-

343

and low-dose-rate

irradiation

Slope+

Dose rate (Wmin)

TC&* (GY)

5.05 5.05 5.05 5.05 1.25 1.25 0.54 0.54 0.03

73 (70-75) 79 (76-82) 99 (91-104) 118 (110-121) 87 (84-90) 99 (95-103) 68 (60-75) 101 (94-l 14) 124(109-147)

Dose modification factort

(%/GY) 7.4 9.4 6.0 7.8 7.2 4.3 3.4 2.3 2.2

1.25 1.05 1.43 (1.22-l .49) 1.17 (1.07-1.30) 1.72 (1.49-2.00) 1.16 (1.01-1.33)

(3.4-l 1.0) (2.4-6.3) (1.6-5.3) (1.1-3.5) (0.6-3.8)

tumor control dose with 95% confidence interval. of the dose-response curve at the TCDSo, (dP,/dD 15o)as defined by Fischer & Moulder (5). of TCDcn values far LDR (0.03 Gv/min) and CDR irradiation. with 95% confidence interval. from M&lder et al (21) and Fischer & boulder (5).

chamber in acrylic plastic phantoms. The dose reported are for the midline of the tumor or the abdomen. In the CDR tumor studie:s the dose fall-off across the tumor was less than 10%. For the lower hemi-body irradiations, the entrance and exit: doses differed from the midline dose by 25%, and the doses to the two kidneys were 12% above and below the midline dose.

tion

Normal tissue tolerance In the lower hemi-body irradiation studies animals were killed when morbid, and precise causes of death were not determined for individual animals. Two patterns of morbidity were observed. At high doses, animals suffered severe weight loss and dehydration during or immediately after irradiation. Animals which survived for more than 7 days after irradiation regained weight and became grossly normal. This early morbidity was presumed to be due to acute gastrointestinal (GI) damage. A second wave of progressive morbidity began 6 to 8 weeks after the end of treatment. This late morbidity was characterized by moderate weight loss and dehydration, elevated blood urea nitrogen (BUN), proteinuria, and decreased urine creatinine. Radiation nephritis is clearly a major cause of this late morbidity (23), but chronic GI injury cannot be ruled out for some animals. Morbidity was attribut’ed to GI damage if the animals died either during treatment or within 7 days of the end of treatment. Animals dying during treatment were assigned the dose that had been planned for them, rather than the dose they had received at the time of death. Late morbidity was defined as morbidity requiring sacrifice of the animal within 100 days of the start of treatment. Fifty percent effective doses (ED& were calculated and compared by probit statistics (4). For assessment of renal function, blood and urine were collected and urine creatinine, BUN, and urine protein were determined by commercial assay kits. Although urine creatinine, BUN, and urine protein are only general indicators of renal damage, they correlate well after renal irradiation with measurements of serum creatinine, urine

volume, urine N-acetyl-glucosamine to creatinine ratio (13,24), and hypertension (35). Dose-response curves for urine creatinine were compared by linear regression analysis (2).

RESULTS Fractionated LDR and CDR tumor irradiation Animals with BAl 112 tumors were treated with fractionated LDR (0.03 Gy/min) irradiation using 9 Gy per fraction (Table 1, Fig. 1); the TCDSOwas 124 Gy. Animals were also treated with fractionated CDR (0.54 Gy/min) irradiation under the same protocol and at a similar dose per fraction; the TCDSOwas 68 Gy (Table 1, Fig. 1) for a dose modification factor (DMF) of 1.72 compared to the 1.0,

.

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120

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140

Total Tumor Dose (Gy) Fig. 1. Tumor control dose-response curves for fractionated conventional- and low-dose-rate irradiation of BA 1112 sarcomas. Conventional-dose-rate (CDR) animals were treated at 0.54 Gy/ min with 5-10 fractions of 9.7 Gy/fraction (O), or lo-19 fractions of 6.25 Gy/fraction (m). Low-dose-rate (LDR) animals were treated at 0.03 Gy/min with lo-16 fractions of 9 Gy/fraction (0). All irradiations used the jigs and collimator designed for the LDR studies. TCDso values are shown with 95% confidence intervals.

344

I. J. Radiation Oncology 0 Biology 0 Physics

LDR regimen. Because this CDR treatment used a smaller number of fractions (5-10 fractions) than the LDR treatment (lo-16 fractions), this DMF includes both a fractionation and a dose-rate component. To isolate the doserate component, a second CDR regimen was tested (Table 1, Fig. 1) using a smaller dose per fraction (6.25 Gy) and a larger number of fractions ( 10-19). For this CDR regimen, the TCDso was 10 1 Gy, for a DMF of 1.16 compared to the LDR regimen. The fractionated CDR protocol used in these studies differed in a number of ways from the protocols used in previous studies (5, 18, 2 1, 25). The dose rate was lower than that used previously (1.25-5.05 Gy/min), since the 6-animal collimator required a larger treatment field and a longer treatment distance. The collimator used in these studies did not allow positioning that was as precise as the single-animal collimator used previously; combined with the longer irradiation times, this increased the possibility of geographical misses. In addition, the tumor control dose-response curves were generated by varying the number of fractions, rather than by varying the dose per fraction. To evaluate the effect of these protocol changes, two additional tumor control studies were done which used 12 and 20 fractions at a dose-rate of 1.25 Gy/min, and which used the jigs and treatment techniques used in previous studies (Table 1, Fig. 2). Figure 2 shows the doseresponse curves for these CDR treatments compared to the dose-response curves for the CDR treatments used to determine DMF values for the LDR irradiations. Figure 3 shows the TCDso values for these CDR schedules plus l.O~~....,

0.8 -

0.6 -

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August 1990, Volume 19, Number 2

is s g s 0

120 110 100

8 E

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Number of Radiation Fractions Fig. 3. Fifty percent tumor control doses (TCDSo) for the irradiation schedules shown in Figures 1 and 2. Animals were treated at 1.25 Gy/min (A), 0.54 Gy/min (m), or 0.03 Gy/min (0). For comparison, TCDso values are shown for previous studies in which animals were treated at 5.05 Gy/min (0) (21). TCDso values are shown with 95% confidence intervals.

TCDSOvalues for animals treated at 5.05 Gy/min in previous studies (2 1). The TCDso for the CDR schedules which used lo-19 fractions at 0.54 Gy/min did not differ significantly from the TCDso values for the schedule which used 20 fractions at 1.25 Gy/min, or from the schedule that used 15 fractions at 5.05 Gy/min (Table 1, Fig. 3). However, from Figure 2 and Table 1 it is clear that the slopes of the doseresponse curves for treatments with the six-animal collimator designed for the LDR irradiations were shallower (2.2-3.4% per Gy) than the dose-response curves for the treatments that were done in the more conventional single animal collimator (4.3-9.4% per Gy). This indicates that there was more dose heterogeneity in the LDR set-up. Although this heterogeneity does not appear to have had a major affect on the TCDso values (Fig. 3), it is probable that TCDSO values determined with the six-animal collimator are slightly overestimated.

0.4 -

Fractionated LDR and CDR lower hemibody irradiation

0.2 -

2 a

o.ocI. 50

1”. 60

70

.

5



80

90

.





100

110

.

’ 120

1

Total Tumor Dose (Gy) Fig. 2. Tumor control dose-response curves for fractionated CDR irradiation of BAl 112 sarcomas. Animals were treated at 1.25 Gy/min with 12 (0) or 20 (m) fractions using the techniques developed for previous studies (18, 25) or were treated at 0.54 Gy/min with 9.7 Gy/fraction (El), or 6.25 Gy/fraction (0) using the techniques developed for these LDR studies. TCDso values are shown with 95% confidence intervals.

* The error limits shown for dose modification factors (DMF) and therapeutic gain factors (TGF) are 95% confidence intervals.

When animals were treated with lower-hemibody irradiation using 12-18 fractions, the acute (7 day) ED5,, was 109 Gy for LDR irradiation, and 63 Gy for CDR irradiation (Table 2, Fig. 4). Based on time and symptoms, the acute deaths were due to gastrointestinal damage. The DMF for this acute GI damage was 1.74 (1.52-l .95).* The ED50 for late (100 days) morbidity was 62 Gy for LDR irradiation and 35 Gy for CDR irradiation (Table 2, Fig. 5). The DMF for late morbidity was 1.80 (1.572.19); this morbidity could be due to either late GI damage or radiation nephritis (23). To clarify the cause of this

Fractionated low-dose-rate radiotherapy 0 J. E. MOULDER Table 2. Normal tissue tolerance doses for fractionated conventional-

Tissue endpoint

345

et al.

and low-dose-rate irradiation schedules

Number of fractions

Dose per fraction (Gy)

Dose rate (Gy/min)

Tissue tolerance dose (Gy)

12-16 12-18 12-16 12-17 10-14 lo-16

3.0-4.5 4.5-7.2 2.1-3.1 3.8-6.8 2.6-3.2 3.7-4.4

2.10 0.03 1 2.10 0.03 1 2.10 0.03 1

63.1 (58.7-75.9)+ 109.0 (100.5-l 32.4)+ 34.7 (28.5-37.8)* 62.3 (54.8-73.8)$ 27.1 (24.6-30.9)” 5 1.9 (48.2-63.2)§

Acute lethality Late morbidity Chronic nephritis

Dose modification factor* 1.74 (1.52-1.95) 1.80 (1.57-2.19) 1.91 (1.68-2.35)

* Ratio of tissue tolerance doses, with 95% confidence interval. + 50% lethal dose, with 95% confidence interval, for deaths during treatment or within 7 days of the end of treatment. z 50% effective dose, with 95% confidence interval, for morbidity within 100 days of the start of treatment. 5 Dose to reduce urine creatinine level to 75 mg/dl 90 days after the start of treatment, with 95% confidence interval.

late morbidity, renal function tests were performed 90 days after the start of irradiation. At doses close to the EDso for morbidity at 100 days, urine creatinine levels were severely depressed (Fig. 6) and BUN and urine protein levels were elevated, indicating that radiation nephritis is at least a major cause of the late morbidity. Figure 6 shows dose-response curves for urine creatinine levels in animals that received LDR and CDR lower hemibody irradiation. The DMF for this endpoint was 1.9 1 (1.68-2.35).

Despite differences in the type of tissue, the dose per fraction, and the time of assessment, the DMF values for normal tissue tolerance did not differ significantly from one another, although DMF values tended to increase with decreasing tissue tolerance doses (Table 2). The average tissue DMF was 1.80 ( 1.60-2.15). I

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100

110

120

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1

130

Total Hemi-Body Dose (Gy) Fig. 4. Dose-response curves for acute mortality (death during or within 7 days of the end of treatment) for fractionated conventional- and low-dose-rate lower hemi-body irradiation of WAG/Rij rats. Conventional-dose-rate animals were treated at 2.1 Gy/min with 12-16 fractions of 3.0-4.5 Gy/fraction (0). Low-dose-rate animals were treated at 0.03 12 Gy/min with 1218 fractions of 4.5-7.9 Gy/fraction (0). EDSo values are shown with 95% confidence intervals.

+ The therapeutic gain factor was defined as the DMF for normal tissue tolerance divided by the DMF for tumor control.

Therapeutic gain for fractionated LDR radiotherapy

In theory, DMF values could be calculated for either equal dose per fraction or for equal numbers of fractions. However, for the determination of therapeutic gain factor (TGF)+ values calculations needed to be based on equal number of fractions, since the endpoints could not all be assessed at the same dose per fraction. The experimental design makes it difficult to determine precisely the tumor control DMF for equal numbers of fractions, as no CDR regimen reached TCDSO in exactly the same number of fractions as the LDR regimen. The best comparison is with the CDR regimen, which used the same collimator as the LDR regimen and a slightly larger number of fractions; for this regimen the DMF was 1.16 (1.01-1.33). The number of fractions required to reach the TCDSo was 16 ( 15- 18) in this CDR regimen compared to 14 ( 12- 16) 1.01.

20

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50

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60

70

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90

100

Total Hemi-Body Dose (Gy) Fig. 5. Dose-response curves for late morbidity (within 100 days of the start of treatment) for fractionated conventional- and lowdose-rate lower-hemibody irradiation of WAG/Rij rats. Conventional-dose-rate animals were treated at 2.1 Gy/min with I2- 16 fractions of 2. I-3.3 Gy/fraction (0). Low-dose-rate animals were treated at 0.03 12 Gy/min with 12-17 fractions of 3.8-6.8 Gy/fraction (0). EDSo values are shown with 95% confidence intervals.

I. J. Radiation Oncology 0 Biology 0 Physics

346

200

-

I 40

60

80

Total Renal Dose (Gy) Fig. 6. Dose-response curves for radiation nephritis 90 days after the start of treatment for fractionated conventionaland lowdose-rate lower-hemibody irradiation of WAG/Rij rats. Urine creatinine (an index of renal function) is shown for animals treated at 2.1 Gy/min with IO-14 fractions of 2.6-3.3 Gy/fraction (0) or treated at 0.03 12 Gy/min with lo-16 fractions of 3.8-4.4 Gy/fraction (0). Urine creatinine values are shown with 95% confidence intervals.

in the LDR regimen. To estimate the effect that this difference in fraction number could have on the tumor DMF calculation, we calculated (from the data in Fig. 3) that the TCDso for fractionated CDR irradiation increased by 2.9 Gy per fraction. Thus, a CDR regimen that used 14 fractions would have a TCDSO value 5.8 Gy lower than a CDR regimen that used 16 fractions. This correction would increase the tumor DMF to 1.23 (1.01-l .41). A more direct way of estimating the tumor DMF would be to compare the TCDSO for the LDR regimen to the best fit line through all the CDR regimens shown in Figure 3; this gives a tumor DMF of 1.32 (1.06-l 53). Based on these tumor DMF estimates, we have calculated TGF values for the three endpoints. The TGF was 1.35 ( 1.15- 1.70) for acute lethality, 1.40 ( 1.15- 1.85) for late morbidity, and 1.50 (1.25-2.00) for renal function. The average TGF value for all tissue endpoints was 1.4 (1.2-1.8). DISCUSSION There are little data in the literature on normal tissue tolerance for fractionated LDR irradiation. Huczkowski and Trott (14, 15) measured a DMF of 1.1 for jejunal crypt cells treated at 0.08 Gy/min for 12 fractions, and Henkelman et al. (11) measured a similar DMF for skin tolerance after 10 fractions delivered at 0.06 Gy/min. Tarbell et al. (33) used three fractions of 0.05 Gy/min total body irradiation and measured DMF values of 1.O1.1 for GI, lung, and bone marrow tolerance. The DMF values of 1.7-1.9 measured for fractionated LDR hemibody irradiation in this study are in striking contrast to the above data. These DMF values, however, are similar to those reported for 0.02-0.03 Gy/min single-fraction

August 1990, Volume 19, Number 2

irradiation of lip mucosa (32) lung (3), intestine ( 14, 34) and kidney (23). There are differences between our study and those of Huczkowski and Trott ( 14, 15) Henkelman et al. (1 I), and Tarbell et al. (33) that could account for the differences in DMF values. The study reported here used a longer overall treatment time (22-40 days vs 2- 10 days); this allowed for a large amount of proliferation, and hence we required a larger dose per fraction than that used by Huczkowski and Trott (14, 15) or Tarbell et al. (33). This higher dose per fraction, coupled with a lower dose rate (0.03 Gy/min vs 0.05-0.08 Gy/min), may increase the amount of repair that occurs in the LDR regimen. The high DMF value for renal tolerance was not unexpected, as this tissue has a lower LY/~ ratio than either skin or jejunum (36) and should be better protected by LDR. To study the question we are investigating normal tissue tolerance for fractionated LDR therapy delivered over shorter periods of time and at other dose rates. We are not aware of other tumor studies using fractionated LDR irradiation. The DMF value found in this study ( 1.O- 1.5) was lower than those reported by Peschel et al. (26) for single fraction LDR irradiation of BA 1112, by Kal and Barendsen (16) for single fraction LDR irradiation of a related tumor line, and by Fu et al. (8) for single fraction LDR irradiation of EMT6. Hill and Bush ( 12) reported a similar low DMF value for single fraction irradiation of KHT. Factors other than dose rate may have affected the DMF values measured in this study. We have not corrected the doses in the 6oCo LDR studies for RBE effects, since we do not know, and cannot practically measure, the RBE for fractionated LDR irradiation, Presumably, the RBE is less than one, so that the DMF values for the dose rate comparison are overstated by an unknown factor. This RBE issue will not affect the TGF values providing that the RBE values for fractionated LDR irradiation are the same for tumors and normal tissues. While the use of different types of radiation in the LDR and CDR arms complicates interpretation of the study, this contrast of conventional dose-rate X rays to low dose-rate 6oCo y rays is the comparison that is relevant to clinical fractionated external beam LDR trials (27-30). The DMF values may also have been affected by our use of treatments from alternate sides on alternate days. When treatment is done from alternate sides on alternate days, tissue that is located away from the midline is treated with unequal fractions. Theoretically, the use of unequal fractions would be expected to increase sublethal damage repair and thus increase tolerance. This would not have affected DMF values for tumor control since the fall-off of dose across the tumors is small and roughly equal (7% vs 10%) in the LDR and CDR arms of the study. In the CDR hemi-body irradiations, where there was appreciable dose fall-off, calculations indicate that the cell kill would not have been decreased by more than 5% by this variation in dose per fraction. Therefore this factor is unlikely to

Fractionated low-dose-rate radiotherapy 0 J. E. MOULDER

have appreciably affected the tissue DMF values measured in this study. The single-fraction LDR data indicate that LDR irradiation will generally protect normal tissues better than tumors. For single-fraction irradiation at 0.02-0.03 Gy/ min normal tissue DMF values are usually in the 1.8-2.3 range (3, 14, 23, 32, 34); bone marrow is the major exception with DMF values of 1.0-l .2 (1, 8, 33). Tumor DMF values cover a broad range between 1.1 and 1.8 (8, 12, 16, 26). These data imply a therapeutic gain factor (TGF) of 1. l- 1.7 for single-fraction LDR irradiation. The TGF value measured in this study for fractionated LDR irradiation is at the upper end on this range. The magnitude of this therapeutic gain is illustrated by the observation that fractionated LDR therapy could control some BA 1112 tumors with lower hemi-body irradiation, since the acute morbidity EDSo (Table 2) is equal to the TCDZO (Fig. 1). With fractionated CDR therapy, on the other hand, no tumors would be controlled by lower hemi-body irradiation, since the acute morbidity EDg0 (Fig. 4) is less than the TCDlo (Fig. 1). We hypothesize that the high TGF found for fractionated LDR (in comparison to single-fraction LDR) is due to a smaller tumor control DMF rather than to a larger normal tissue DMF. Whly would fractionating the LDR therapy provide less protection of the tumor? The most obvious explanation is tllat hypoxia is not as important during LDR irradiation as during CDR irradiation, either because of a low OER for LDR irradiation, or because the tumor is reoxygenating during irradiation. The ob-

etal.

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servations that hypoxic cell sensitizers (7, 17) and perfluorochemical emulsions (20) are less effective with single-dose LDR irradiation than with CDR irradiation provide indirect support for this explanation. We intend to study this question directly by measuring the hypoxic fraction during LDR and CDR regimens, and by determining whether regimens designed to sensitize hypoxic cells will work as well during fractionated LDR therapy as they do during fractionated CDR therapy (22). The model provides an experimental system in which to ask some practical questions about the use of fractionated LDR radiotherapy. For example, it is critical for the clinical use of fractionated LDR therapy to know what dose rate is needed to achieve the therapeutic gain associated with LDR therapy; the higher the dose rate that can be used, the more practical and widely applicable LDR teletherapy will be. A related question is whether LDR teletherapy can be added as a boost to a conventional CDR regimen, without losing its therapeutic advantage. These issues can be directly addressed in this model system. This study shows that there is an experimental as well as a theoretical basis for anticipating a therapeutic benefit from the use of external beam fractionated LDR radiotherapy, and should provide encouragement to those conducting the difficult clinical trials. The data also imply that the recognized therapeutic efficacy of brachytherapy is not due solely to the high localized dose; on-going clinical studies with high dose-rate brachytherapy should clarify this issue.

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H. R. Biologic basis Cancer 55:2086-2095;

for altered 1985.

fractionation

Tumor and normal tissue tolerance for fractionated low-dose-rate radiotherapy.

Radiobiological evidence suggests that an improved therapeutic ratio might be achieved through the use of smaller than conventional dose fractions. Th...
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