Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course

Abstract

Purpose: In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from (131)I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with (177)Lu-DOTA(0)-Tyr(3)-octreotate ((177)Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit.

Methods: The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined.

Results: Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0 × 10(9)/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67 ± 7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq (177)Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients.

Conclusion: The incidence of subacute haematological toxicity after PRRT with (177)Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from (131)I, seems not to be valid for PRRT with (177)Lu-DOTATATE.

Keywords: 177Lu-DOTATATE; Bone marrow; Dosimetry; PRRT; Toxicity.

Fig. 1

Generalized compartment model for the biodistribution of ¹⁷⁷Lu-DOTATATE in humans. Compartments (C1 to C5) represent different organs. Flow in both directions between compartments is represented by kinetic transfer components, k(i,j). The shaded grey circles represent input (radioactivity) data and the open grey circle represents modelled output. Injection is a simulated bolus of ¹⁷⁷Lu-DOTATATE in the blood compartment

Fig. 2

Venn diagram of haematological toxicity (grade 3/4) in 34 out of 320 patients treated with a median cumulative dose of 29.6 GBq ¹⁷⁷Lu-DOTATATE

Fig. 3

Duration of subacute haematological toxicity (grade 3/4) in 32 of 320 patients treated with a median cumulative dose of 29.6 GBq ¹⁷⁷Lu-DOTATATE: a any toxicity in 32 patients, b thrombocytopenia in 23 patients, c leucocytopenia in 17 patients, and d anaemia in 9 patients (NA results not available during follow-up, Transfusion patients who received blood cell transfusion after grade 3/4 haematological toxicity. Two patients were excluded (see text)

Fig. 4

Platelet counts (a, b), white blood cell counts (c, d) and haemoglobin (e, f) expressed as percentages of the baseline values in relation to bone marrow dose in 23 patients after the first and last treatments with ¹⁷⁷Lu-DOTATATE (circles group-1, 1.85 GBq, n = 4; squares group 2, 3.70 GBq, n = 7; triangles group 3, 7.40 GBq, n = 12). Solid lines is linear regression with 95 % confidence intervals (dotted lines). Significant Spearman’s rank correlation coefficients with (one-tailed) P values in group 3: a r _S = −0.51 with P < 0.05, b r _S = −0.59 with P = 0.02, c r _S = −0.70 with P = 0.01, d r _S = −0.51 with P < 0.05