The study was conducted at the Department of Nuclear Medicine, AIIMS, New Delhi, India. Skeletal metastases patients suffering from pain were referred from the Pain Clinic, Medical Oncology, and Radiation Oncology departments for [177Lu]Lu-DOTA-ZOL pain palliation treatment. This cohort study involved patients who were treated with [177Lu]Lu-DOTA-ZOL for pain palliation between January 2017 and February 2020.
Eligibility Criteria
Eligibility criteria for the [177Lu]Lu-DOTA-ZOL pain palliation treatment included: Histologically confirmed breast, prostate or lung cancers, progressive pain or pain requiring escalation of analgesics, patients with more than one site of pain corresponding to the avid uptake on [68Ga]Ga-DOTA-ZOL PET/CT scan, patients with no prior history of radionuclide pain palliation therapy, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 4, KPS ≥50, patient on or with history of prior bisphosphonates, patients with hematological, kidney and liver function parameters within normal limits which included; baseline haemoglobin of < 9 g/dL, platelet counts: <75,000/μL, leukocyte counts: ≥4 x 109/L, serum creatinine: >1.4 mg/dL, serum bilirubin >3 mg%, glomerular filtration rate (GFR): <50 mL/min per 1·73 m2 body surface area (BSA). Patients with skeletal-related events involving pathological fractures and cord compression were not included.
[177Lu]Lu-DOTA-ZOL Synthesis
The stock solution consisted of 1mg DOTA-ZOL dissolved in 1 ml Ultrapure water to give a concentration of 60 µg/60µL. The 60 µL of DOTA-ZOL was radiolabelled with [177Lu]LuCl3 which was obtained from BRIT, India, in sodium ascorbate buffer, pH 4, in 0.01 M supra pure HCl with a specific activity ranging between 370-740 GBq/mg. The radiolabelled solution was heated at 95°C for 30 minutes. Radiochemical quality control was carried out using the instant thin-layer chromatography method with sodium citrate buffer as the solvent.
Treatment Protocol & Follow-up
[177Lu]Lu-DOTA-ZOL infusion
The patients who fulfilled the eligibility criteria were administered with a fixed dose of 1295 MBq (35 mCi) [177Lu]Lu-DOTA-ZOL. The fixed activity of 1295 MBq of [177Lu]Lu-DOTA-ZOL was extrapolated from our previous [177Lu]Lu-EDTMP phase II data [8]. The infusion involved a dilution of [177Lu]Lu-DOTA-ZOL in 10 mL normal saline (0.9%), which was administered intravenously over 5 minutes, with subsequent flushing of 20 mL normal saline. The entire process was performed on an in-patient basis, and patients were discharged in a few hours of observation if they do not show any adverse reaction to [177Lu]Lu-DOTA-ZOL. Figure 1 shows biodistribution and uptake of [177Lu]Lu-DOTA-ZOL therapy in a patient with skeletal metastases from prostate cancer, while Figure 2 gives similar data of [177Lu]Lu-DOTA-ZOL therapy in a patient with skeletal metastases from breast cancer.
Follow-up
The treatment was repeated if necessary at 3 monthly intervals. post-[177Lu]Lu-DOTA-ZOL administration, patients were assessed at 2, 4, 8, and 12 weeks. Patients were assessed for laboratory parameters and the adverse events were recorded according to the National Cancer Institute for Common Toxicity Criteria version (CTC) 5.0 [28]. The Visual analog score (VAS) [29], global assessment pain score (AS), Karnofsky performance status (KPS) [31, 32], and assessment of pain relief were recorded in the patient case-files on each visit. Patients were instructed to maintain a diary and document the pain relief parameters such as initiation of pain relief, duration of pain relief, time of increase and/or recurrence of pain, decrease or increase in the consumption of pain killers.
Treatment Response Assessment
Primary Outcome Endpoint
The primary outcome endpoint was response assessment by VAS. According to this criteria, the complete response (CR), partial response (PR), minimal response (MR), and no response (NR) were categorised as >70% reduction, 40 - 70% reduction, 20 - 40% reduction, and <20 % decrease in VAS or increase in pain, respectively [29].
Secondary Outcome Endpoints
Other clinical response assessment parameters involved analgesic score (AS), Karnofsky performance status (KPS), Eastern Cooperative Oncology Group (ECOG) performance status, adverse event profile, and overall survival.
Analgesic scoring was conducted as per the Urological Group of the European Organization of Research and Treatment of Cancer (EORTC, Protocol 30921). As per EORTC protocol, the analgesic score is the product of two five-point scales (the type of analgesic and the frequency of its administration). A decline in the analgesic score was documented as a response to treatment.
Additionally, global response assessment was analysed according to the criteria adopted by Thapa et al. [30] that considered changes in both VAS and analgesic scores (rather than a single parameter). According to the criteria, the present study design considered post-therapy changes in both VAS and analgesic scores on a sliding scale. The global pain assessment criteria accordingly; complete (75% decrease in analgesic score with change in pain score), partial (50% - 75% decrease in analgesic score with a change in pain score), minimal (25% - 50% decrease in analgesic score with a change in pain score), or none (no change in pain score or, 25% decrease in the analgesic score). The KPS was scaled from 100 to 0. The ECOG status ranged from 0 to 5. All adverse events were assessed as per the National Cancer Institute's Common Toxicity Criteria (NCI-CTC) version 5.0. The overall survival (OS) was defined as the time from the initiation of [177Lu]Lu-DOTA-ZOL treatment to the time of death. The death could be attributed to any cause or the last telephonic contact.
Statistical Analysis
The normality of the data was examined by the D'Agostino-Pearson test. The data were presented as mean standard deviation (SD), median, and/or interquartile range (IQR). Unpaired samples t-test (parametric test) or Mann-Whitney U-test (non-parametric test) was performed for two independent patient groups. The paired t-test (parametric test) or Wilcoxon signed-rank test (non-parametric test) were executed to compare parameters at pre-and post-treatment time points. Kaplan-Meier curves analysis was conducted to calculate the overall survival. MedCalc software was used for statistical analyses. P-values ≤ 0.05 was considered significant.