A Practical Methodology for Patient Release After Tositumomab and ¹³¹I-Tositumomab Therapy

Patients and Treatments

Data were analyzed after 157 therapeutic administrations of ¹³¹I tositumomab to 139 patients for the treatment of relapsed or refractory non-Hodgkin’s lymphoma at 2 sites (the University of Michigan Medical Center, Ann Arbor, MI, and the University of Nebraska Medical Center, Omaha, NE) (2–4). These patients were enrolled in phase I/II and phase II studies conducted at the University of Michigan Medical Center, a multicenter phase II study, and a multicenter phase III study. Patients underwent dosimetry studies, followed 7–14 d later by the therapeutic administration. One day before and throughout the dosimetry study and the therapeutic administration, the thyroid was blocked by daily administration of supersaturated potassium iodide. For the dosimetric administration, most patients received a 450-mg infusion of unlabeled tositumomab followed by a 35-mg infusion of trace-labeled ¹³¹I-tositumomab (185 MBq ¹³¹I). After the dosimetric administration, thyroid probes or total-body gamma-camera counts were obtained at least 3 times over the next 6–7 d to determine the patient-specific total-body residence time of the radiolabeled antibody. The residence time, in conjunction with a mass-adjusted S value based on the patient’s height and weight, was used to determine the activity of ¹³¹I-tositumomab needed to deliver a prescribed total-body dose of radiation (patient-specific therapeutic dose) (5). For the therapeutic administration, most patients received an infusion of 450 mg of unlabeled tositumomab followed by an infusion of 35 mg of ¹³¹I-tositumomab with the patient-specific activity of ¹³¹I to deliver the specified total-body radiation dose as described (5). Total-body doses ranged from 25 to 85 cGy in the phase I/II study (2). In all other studies, patients received 75 cGy unless the dose was reduced to 65 cGy because of decreased platelet counts (3). Immediately after the therapeutic administration, patient dose rates at 1 m were measured.

Patient Release Methodology

An algorithm for determining patient release after tositumomab and ¹³¹I-tositumomab therapy was developed on the basis of a retrospective analysis of patient data. Patients were eligible for release after completing a 3-step patient-release protocol. First, a patient interview must be conducted to evaluate the patient’s living and working conditions to determine whether the patient is able to care for himself or herself and whether the patient’s living or working arrangements are such that he or she can maintain a safe distance from family members and coworkers. Second, the patient-specific dose calculation, based on patient-specific total-body residence time (measured after the dosimetric administration) and the dose rate at 1 m (measured after the therapeutic administration), must be performed. For this analysis, values were standardized to the maximum tolerated total-body dose of 75 cGy. Thus, releasability for all patients was determined as if they had received a 75-cGy total-body dose.

Some common lifestyle behaviors, such as sleeping in a common bed or riding in a car, may increase the exposure of individuals to ¹³¹I. Therefore, the final step in the release process must involve the generation of written instructions regarding radiation safety precautions to maintain doses to other individuals of <5 mSv and as low as reasonably achievable (6). The instructions should specify how long these precautions must be followed. Therefore, the times necessary to follow these instructions were determined for each patient. Before patient release, the physician must have a high degree of confidence that the instructions will be followed. For released patients, the instructions were discussed before release and were given in writing to the patient.

Patient-Specific Dose Calculation to Determine Patient Releasability

Before patient release from the nuclear medicine facility, a patient-specific dose calculation must be performed to ensure that the maximally exposed individual will receive a radiation dose of <5 mSv. The dose calculation was based on the measured total-body residence time (τ_TB) and dose rate at 1 m ([mSv/h]_1m ([mrem/h]_1m)), obtained for each patient as per NRC guidance in Appendix B of Regulatory Guide 8.39 (7). The calculation also requires inclusion of a term to account for the fact that during the initial hours (approximately 3 h) after administration of the radiolabeled material, the patient may not void and the activity is therefore not removed from the body. Failure to include this component would underestimate the dose to total decay (9). The following equation was used for the patient-specific dose calculation for ¹³¹I-tositumomab: Eq. 1 where D_∞ = total dose (mSv) from exposure to γ-radiation; Γ = exposure (dose) rate constant at 1 m (5.95 × 10⁻⁵ mSv m²/MBq h [0.22 mrem m²/mCi h] for ¹³¹I); Q₀ = administered activity (MBq); τ_NV = residence time (h) of the nonvoided component (i.e., 1.443 times the physical half-life of the radionuclide). For ¹³¹I, with a physical half-life of 8.04 d, τ_NV = 278.4 h; and τ_TB = total-body residence time (h) of ¹³¹I-tositumomab.

The total-body residence time, τ_TB, was determined from the total-body time–activity curve obtained during the dosimetric study. This curve may be multiexponential and therefore may have multiple components, such as the sum of the thyroidal and extrathyroidal components for Na¹³¹I as presented in Regulatory Guide 8.39 (7). The time–activity curve was determined in this study to be monoexponential by multiple total-body gamma-camera images of the patient after the dosimetric administration; therefore, Equation 1 was derived on the basis of the observed monoexponential clearance of ¹³¹I-tositumomab from the body. This equation can also be applied to any radionuclide that exhibits monoexponential clearance from the body when the appropriate physical half-life is used for the nonvoided component. (If a radiopharmaceutical exhibits multiexponential clearance from the body, Equation 1 is not applicable.)

Equation 1 uses an initial nonvoiding period of 3 h (9) and an occupancy factor for this component of 0.75; at other times, an occupancy factor of 0.25 is used. This equation can be adapted for nonvoiding intervals other than 3 h by replacing the number 3 in Equation 1 with the appropriate value for the specific radionuclide. Finally, this equation includes the additional conservative assumption that 100% of the ¹³¹I activity does not leave the body during the initial nonvoiding period instead of the 80% value used in Regulatory Guide 8.39 (7).

Substituting the value for the residence time of the nonvoided component of 278.4 h for ¹³¹I, Equation 1 can be simplified to: Eq. 2

Substituting the theoretic dose rate (i.e., the dose rate in air from a point source of activity, Q₀) in mSv/h at 1 m, ΓQ₀, with the measured dose rate at 1 m (mSv/h)_1m, Equation 2 becomes: Eq. 3 Equation 3 was used to estimate the maximum potential dose (TEDE) to individuals exposed to the patient. Equation 3 can also be rearranged to calculate the maximum dose rate at 1 m that will result in a dose of <5 mSv to individuals exposed to the patient: Eq. 4

Equation 4 is the case-specific calculation for patient release, which accounts for the patient occupancy factor and the nonvoiding time period. If the patient’s dose rate at 1 m measured immediately after the therapeutic administration was <5/(2.24 + 0.247 τ_TB), then the patient was releasable. The releasable dose rate is predicated on an occupancy factor of 0.25 at a distance of 1 m and limits the maximal exposure to <5 mSv. Some lifestyle behaviors, such as sleeping in a common bed or extensive traveling with a partner, may result in a higher dose rate or a closer distance. In addition, a patient should limit his or her exposure to children, infants, or pregnant women to <1 mSv. Therefore, released patients were provided written instructions to maintain doses to other individuals of <5 mSv according to the new NRC regulations.

A look-up table has been generated to easily implement the determination of patient releasability based on Equation 4 (Table 1). Releasable dose rates at 1 m, as a function of patient residence time, are listed in Table 1 (an abbreviated look-up table adapted from the physicians’ guidelines (15)). These dose rates represent the maximum allowable for a specific residence time to ensure that no individual will likely receive a dose of ≥5 mSv. A patient is immediately releasable if his or her measured dose rate at 1 m is less than the value given in Table 1 for the patient-specific residence time. This table was generated on the basis of 2 patient-specific factors, residence time and measured dose rate at 1 m, which must be included in the patient’s record at the time of release. Table 1 assumes an occupancy factor of 0.25 and the values in the table must, therefore, be adjusted for occupancy factors other than 0.25. For example, if there is justification for using a lower occupancy factor of 0.125, the values of the dose rates in the table should be doubled. If a higher occupancy factor of 0.5 is necessary, the values in the table should be halved.

The predicted TEDE to the maximally exposed individual was calculated on the basis of the individualized measured parameters of total-body residence time and dose rate using Equation 3.

Patient Instructions Before Release

The patient must limit the time he or she is in contact with other individuals; however, the NRC provides only general guidance for these precautions. The patient’s measured total-body residence time and dose rate can also be used to determine the times necessary for patient instructions to remain in effect to limit certain activities. Therefore, before release, patients also received patient-specific instructions to limit the radiation exposure to family members and caregivers by limiting the time that they are in close contact on the basis of their own residence time and dose rate. The calculations for determining the amount of time necessary for instructions to remain in effect to minimize the radiation dose to sleeping partners, traveling companions, children and pregnant women, and members of the general public are given below.

Dose to Children and Pregnant Women

Assumption: Infants or young children and pregnant women receive no dose before the period without limitations. Normal contact is assumed to be 30 min/d of direct contact at a distance of 0.1 m and 6 h of exposure per day at a distance of 1 m. Eq. 9

For the TEDE to be <1 mSv, the time required before normal contact, t_infant (d), must satisfy: Eq. 10 No limitations for D_∞ < 0.374 mSv

Dose to Members of General Public

Assumption: Members of the general public receive no dose before the period without limitations. Normal exposure for 6 h/d (i.e., an occupancy factor of 0.25) at 1 m is assumed. Eq. 11

For the TEDE to be <1 mSv, the time required before 6 h of exposure per day at 1 m, t_public (d), must satisfy: Eq. 12 No limitations for D_∞ ≤ 1 mSv

Equations 5–12 implicitly assume monoexponential clearance of ¹³¹I-tositumomab from the body. (As was the case for the patient-specific dose calculation, these equations are not applicable for radiopharmaceuticals that exhibit multiexponential clearance from the body.) Further, it is assumed in these equations that the dose rates from the patients at distances, d, other than the measurement distance of 1 m (i.e., 0.1 and 0.3 m) can be approximated by 2 d⁻¹. This approximation was based on actual dose rate measurements obtained at 0.3 and 1 m in 29 ¹³¹I-tositumomab patients, where it was observed that the mean 0.3 m:1 m dose rate ratio was 3.1 ± 1.2 (range, 1.4–6.7) (10). Thus, the 2-d⁻¹ approximation is conservative. The use of the 2-d⁻¹ approximation is further validated by a theoretic calculation under the assumption that the patient simulates a line (rather than a point) source of activity (9,16). In this case, the dose rate is inversely proportional to the distance and directly proportional to the angle, in radians, subtended by the line source; the results of these calculations indicate that 2 d⁻¹ is an accurate approximation for the expected dose rates at 0.3 and 0.1 m. It may be more accurate to simply perform additional dose rate measurements at 0.1 and 0.3 m, as others have suggested (10,17), but we believe that the use of a conservative approximation minimizes the need for these additional measurements, while still maintaining accuracy, thus making the method more practical.

The predicted total effective dose equivalent (D_∞), as determined by Equation 3, is compared with the values in Table 2 (15) (use the column that is greater than or equal to the calculated value for D_∞). To determine the times necessary before sharing a bed, taking long trips, interacting with children and pregnant women, and returning to work (Table 2, instructions 1–4) (15), the value in the appropriate column is multiplied by the patient’s residence time (h) to obtain the duration (d) for each instruction to the released patient. For fractions, the number of days is rounded up to a full day. The durations for instruction numbers 1 and 2 are based on 5-mSv TEDE, whereas those for numbers 3 and 4 are based on 1-mSv TEDE.

Patients

The pertinent demographics and disease characteristics of the patients (n = 139) receiving tositumomab and ¹³¹I-tositumomab therapy are listed in Table 3. Most patients (73%) had low-grade follicular non-Hodgkin’s lymphoma and 92% of the patients were classified as having stage III or stage IV disease. Patients received therapeutic administration of ¹³¹I-tositumomab ranging from 1,221 to 5,957 MBq (33–161 mCi), dependent on dosimetry studies, to deliver a total-body dose of 25–85 cGy. In the phase I/II study, the maximum tolerated total-body dose was established for future studies to be 75 cGy. The mean total-body residence time of ¹³¹I-tositumomab (±SD) was 93.5 ± 15.5 h and ranged from 50 to 129 h (Fig. 1). The coefficient of variation was 16.6%. The mean administered ¹³¹I activity (±SD) was 3,119 ± 1,066 MBq (84.3 ± 28.8 mCi) (range, 1,221–5,957 MBq [33–161 mCi]). The mean dose rate at 1 m (±SD), measured immediately after the therapeutic infusion, was 0.109 ± 0.032 mSv/h (10.9 ± 3.2 mrem/h (range, 0.04–0.24 mSv/h [4–24 mrem/h]) (Fig. 2).

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FIGURE 1.

Distribution of 157 total-body residence times for patients receiving ¹³¹I-tositumomab obtained from 3 to 8 total-body γ-counts obtained over 6–7 d during dosimetric study.

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FIGURE 2.

Distribution of 157 measured dose rates at 1 m obtained immediately after therapeutic administration of ¹³¹I- tositumomab (1,221–5,957 MBq).

Theoretic Versus Measured Dose Rate

The theoretic and measured dose rates at 1 m immediately after infusion were compared. The theoretic dose rate at 1 m was calculated by multiplying the administered activity of ¹³¹I (MBq) by the known dose equivalent rate constant for ¹³¹I of 5.95 × 10⁻⁵ mSv/MBq h (0.22 mrem/mCi h) at 1 m. The correlation between the theoretic and the observed dose rate was good (r = 0.858). However, because the theoretic dose rate does not account for photon attenuation and nonpoint–source distribution of the ¹³¹I activity within the patient, it was consistently higher than the observed dose rate (Fig. 3). The mean observed dose rate (±SD) was 60% ± 10% of the theoretic dose rate (range, 37%–90%). Because the observed dose rates after administration of ¹³¹I-tositumomab were approximately 60% of the theoretic rates, the initial dose rate (mSv/h) at 1 m immediately after therapy is expected to be 3.57 × 10⁻⁵ (0.60 × 5.95 × 10⁻⁵) times the administered activity of ¹³¹I (MBq) (initial dose rate [mrem/h] at 1 m is 0.132 [0.60 × 0.22] times the administered activity [mCi]). Larger patients had a slightly lower measured dose rate and smaller patients had a slightly higher measured dose rate.

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FIGURE 3.

Comparison of measured and theoretic dose rate at 1 m after therapeutic administration of ¹³¹I-tositumomab (n = 157). Theoretic dose rate is calculated using dose equivalent rate per unit activity of ¹³¹I (5.95 × 10⁻⁵ mSv/MBq h [0.22 mrem/mCi h] at 1 m), which is intended for point source of radioactivity in air and not distributed source in patient. Correlation between 2 measures was 0.858, with measured dose rate, on average, 60% of theoretic dose rate.

The percentage difference between the theoretic and observed dose rates increased with higher administered activity (Fig. 3). The measured dose rate at 1 m per unit activity infused predictably decreased with increasing size, expressed as body mass (Fig. 4), or body surface area because of increasing photon attenuation.

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FIGURE 4.

Plot of measured dose rate per MBq (mCi) versus patient mass obtained at 1 m immediately after therapeutic dose of ¹³¹I-tositumomab. Measured dose rates per MBq (mCi) were below theoretic dose rate per mCi and tended to be lower in patients with greater mass (r = −0.547).

Radiation Doses to Maximally Exposed Individuals

The mean estimated doses to individuals maximally exposed to patients (i.e., TEDE) were calculated using Equation 3 on the basis of a 0.25 occupancy factor at 1 m. These estimates revealed a mean TEDE (±SD) of 3.06 ± 0.56 mSv (306 ± 56 mrem) (range, 1.95–4.96 mSv [195–496 mrem]) (Fig. 5). All patients were releasable on the basis of the predicted dose to the maximally exposed individuals.

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FIGURE 5.

Distribution of 157 maximum predicted doses to individuals exposed to patients receiving tositumomab and ¹³¹I-tositumomab therapy after immediate release following therapeutic administration. Maximum doses are based on occupancy factor of 0.25 at 1 m.

The mean recommended times to limit close contact with others were calculated for the entire patient population on the basis of the total-body residence times and measured dose rates (Table 4). The mean time to avoid sleeping in a common bed for the entire patient population was 7.8 d (range, 2.8–14.6 d). The mean times to avoid close travel for 4 h, daily contact with infants or pregnant women, and daily close contact of >6 h with individuals other than the caregiver or family member were 0.3, 8.1, and 4.3 d, respectively.

The following is a practical example of the generation of the instructions in Table 4 using the values listed in Table 2. After a 185-MBq (5 mCi) dosimetric administration of ¹³¹I-tositumomab, the residence time for a patient was determined to be 73 h. Immediately after the therapeutic administration of ¹³¹I-tositumomab, the dose rate at 1 m from the patient was 0.18 mSv/h. Using Equation 3, the TEDE, D_∞ = 0.18 mSv/h × (2.24 + 0.247 × 73 h), was determined to be 3.65 mSv. Therefore, the 3.75-mSv column in Table 2 was used to calculate the duration for each instruction. The times necessary for the instructions to remain in effect for this patient would be as follows:

• Sleep in a separate bed (at least 2-m separation) = 73 × 0.102 = 8 d

• Do not take a long trip (≥4 h) sitting near others (e.g., car, train, airplane, bus) = 73 × 0.011 = 1 d

• Stay at least 2 m from children and pregnant women = 73 × 0.096 = 7 d; if no direct contact with children or pregnant women = 73 × 0.055 = 4 d

A physician may want to limit the dose to infants or young children and pregnant women to 1 mSv. Normal contact (after the avoidance period) with children and pregnant women is assumed to be 30 min/d of direct contact and 6 h/d at 1 m. In this case, the instruction duration is obtained from Table 2, row 3. If no direct contact is planned, the instruction duration is obtained from Table 2, row 4.

• Minimize time spent in close contact with others and delay return to work = 73 × 0.055 = 4 d

A physician may also want to limit the dose to members of the general public to 1 mSv (and apply the 5-mSv limit only to adult, nonpregnant family members or the maximally exposed individual). In this case, the instruction duration is obtained from Table 2, row 4.