Longitudinal plasma and urinary SP-D and sRAGE during BEP chemotherapy in germ cell tumours

Bleomycin-induced pulmonary toxicity remains a significant complication of curative BEP chemotherapy for germ cell tumours, and no validated circulating biomarker enabling individual risk prediction or early detection of lung damage is currently available.

This exploratory two-centre cohort study enrolled 60 patients with germ cell tumours receiving therapeutic three or four cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy. A separate cohort of 18 patients with germ cell tumours receiving adjuvant single-cycle BEP was analysed independently. Plasma and urinary concentrations of surfactant protein D (SP-D) and soluble receptor for advanced glycation end-products (sRAGE) were evaluated before, during, and after BEP chemotherapy in relation to pulmonary toxicity, diffusing capacity of the lung for carbon monoxide (DLCO), pulmonary metastases, renal function, inflammatory indices, grade ≥3 neutropenia, febrile neutropenia, and other non-pulmonary toxicities.

Documented pulmonary toxicity developed in thirteen patients during or after BEP chemotherapy. Baseline plasma SP-D and sRAGE were not significantly associated with pulmonary toxicity (OR per doubling 0.60 [95% CI 0.27-1.37]; p=0.230 and OR 1.20 [95% CI 0.55-2.62]; p=0.640, respectively). The longitudinal increase of plasma SP-D during BEP chemotherapy was statistically significant (p=0.00018; n=30 with complete measurements), with a more pronounced increase associated with HRCT-confirmed pulmonary toxicity. Higher baseline urinary SP-D was significantly associated with lower post-treatment DLCO (Spearman coefficient rho=-0.609; p=0.001; FDR q=0.014). Plasma SP-D trajectories differed significantly according to the presence of pulmonary metastases (time × metastases interaction: p=0.012; adjusted p=0.027). Maximum plasma sRAGE was statistically significantly associated with neutropenia and/or febrile neutropenia during BEP chemotherapy (OR per doubling 12.13 [95% CI 2.59-56.93]; p=0.0016; FDR q=0.013), with this association remaining significant after correction for multiple testing.

In patients with germ cell tumours receiving BEP chemotherapy, SP-D showed potential as a candidate monitoring biomarker of pulmonary injury during BEP chemotherapy. Greater SP-D increases were associated with HRCT-documented pulmonary toxicity in an exploratory analysis, whereas higher baseline urinary SP-D was significantly associated with impaired diffusing capacity of the lungs after treatment completion. Higher maximum plasma sRAGE was associated with neutropenia and/or febrile neutropenia. These results support prospective validation of compartment-specific monitoring of SP-D and sRAGE during BEP chemotherapy.