Dosimetry-based high-activity therapy with ¹³¹I-metaiodobenzylguanidine (¹³¹I-mIBG) and topotecan for the treatment of high-risk refractory neuroblastoma

Abstract

Purpose

Patients with high-risk neuroblastoma have an increased risk of recurrence and relapse of disease and a very poor prognosis. ¹³¹I-metaiodobenzylguanidine (¹³¹I-mIBG) in combination with topotecan as a radiosensitizer can be an effective and relatively well-tolerated agent for the treatment of refractory neuroblastoma. The aim of this retrospective study was to evaluate response and outcome of combined therapy with ¹³¹I-mIBG and topotecan.

Methods

Ten patients, between 3 and 20 years of age, were included. Nine patients had been refractory to several lines of chemotherapy and radiotherapy. One patient with a very high-risk neuroblastoma had received only induction therapy. Response was graded according to the International Neuroblastoma Staging System.

Results

Regarding treatment response, two patients achieved complete remission, one with relapse at 16 months, five achieved a partial remission, four showed progression at between 1 and 18 months; two showed stable disease with progression at between 1 and 5 months, and one showed progressive disease. Eight of the ten patients died with overall survival between 4 and 63 months, and two patients were still alive without disease at the time of this report: 52 and 32 months (patient had received only induction therapy). Acute and subacute adverse effects were mainly haematological, and one patient developed a differentiated thyroid cancer.

Conclusion

In patients with high-risk refractory neuroblastoma, administration of high activities of ¹³¹I-mIBG in combination with topotecan was found to be an effective therapy, increasing overall survival and progression-free survival. Further studies including a larger number of patients and using ¹³¹I-mIBG for first-line up-front therapy are warranted.

Appendix

To obtain the whole-body absorbed dose in the treatments, dose-rate measurements were performed with a pressurized μR ion chamber survey meter (Inovision Model 451P) at 1 and 2 m from the standing patient. At both distances, measurements were acquired with the patients facing and turning their back to the meter, and the geometrical mean of the two measurements was calculated. All measurements were taken by trained staff, taking care to reproduce the same geometry each time. A background measurement was taken prior to treatment. The first measurement was taken immediately after the administration of the ¹³¹I-mIBG to obtain the reading corresponding to the whole activity administered, and before the patient emptied the bladder, at a precisely recorded time. The rest of the measurements were taken approximately every 2 h during the first day, every 4 h during the second day and every 6 h during the remaining days, trying to acquire them after a bladder void.

Whole-body absorbed dose was calculated according to standard MIRD methodology, in which D_wb is given by the expression:

$$ {D}_{\mathrm{wb}}={A}_{\mathrm{c},\mathrm{wb}}{S}_{\mathrm{wb}\leftarrow \mathrm{wb}} $$

where A_c,wb is the cumulated activity in the whole-body, and S_{wb ← wb} is the S factor for the whole body.

The cumulated activity in the whole body, A_c,wb, was calculated by integrating the activity–time curve. The curve fitting was performed considering three exponential decay phases of the activity in the whole body, obtaining the next expression for A_c,wb [30]:

$$ {A}_{\mathrm{c},\mathrm{wb}}=\sum \limits_{i=1}^3\frac{A_i-{A}_{i+1}}{\lambda_i} $$

where A₁ is the administered activity. A_i is the activity value at the change from phase i − 1 to phase i, and λ_i is the effective decay constant of phase i.

The S factor, S_{wb ← wb}, was calculated using the expression:

$$ {S}_{\mathrm{wb}\leftarrow \mathrm{wb}}=1.34\times {10}^{-4}{m_{\mathrm{p}}}^{-0.921}\mathrm{GyMB}{\mathrm{q}}^{-1}{\mathrm{h}}^{-1} $$

where m_p is the patient’s weight in kilograms. This expression was obtained by interpolating data from new-born, one-year-old, five-year-old and adult phantoms [42].

The accuracy of the absorbed dose estimate will depend largely on the accuracy of the measurements. A gross estimation gave an uncertainty value for our absorbed dose of ±20% [43].

The activity to administer in the second therapy was obtained by performing a straightforward calculation from the whole-body absorbed dose in the first therapy.