Neuronal autoantibody titers in the course of small-cell lung carcinoma and platinum-associated neuropathy

The aims of this study were to investigate, in patients with newly diagnose d small-cell lung carcinoma (SCLC), whether or not there may be a relations hip between the presence, type or titer of circulating neuronal autoantibod ies and (i) the extent of SCLC dissemination at presentation, (ii) the deve lopment of peripheral neuropathy during platinum chemotherapy, (iii) surviv al time. We studied stored serum from 58 patients with uncomplicated SCLC w ho had participated in two trials conducted by the North Central Cancer Tre atment Group (NCCTG); 29 had extensive disease and 29 had limited disease. No patient had neuropathy or other neurological or paraneoplastic problems at the time of enrollment but each group included 14 or 15 patients respect ively who developed peripheral neuropathy in the course of chemotherapy. We tested five consecutive serum specimens from each patient in blinded fashi on by (i) an indirect immunofluorescence assay optimized to detect neuron-r estricted nuclear and cytoplasmic antibodies (triple substrate of mouse cer ebellum, gut and kidney), and (ii) immunoprecipitation assays to detect neu ronal Ca2+-channel-binding antibodies (N-type and P/Q-type). Sera that were positive by immunofluorescence were analyzed further by Western blotting. Neuronal autoantibodies were significantly more frequent in patients who ha d limited SCLC at presentation (12/29 or 41% positive) than in those with e xtensive SCLC (5/29 or 17% positive, P = 0.02). Neuronal autoantibodies of nuclear or cytoplasmic specificity were found in 50% of the seropositive pa tients with limited SCLC (21% of the total group), but in no patient with e xtensive SCLC (P = 0.01). The frequency of neuronal autoantibodies did not differ significantly among patients who did and did not develop peripheral neuropathy. Titers fell progressively during chemotherapy and did not rise again when peripheral neuropathy became clinically evident. This argues aga inst a synergism between drug toxicity and neuronal autoimmunity as the mec hanism of platinum-associated peripheral neuropathy. Seropositivity for neu ronal autoantibodies did not affect the survival of patients with either li mited or extensive SCLC. It is conceivable that the immunosuppression atten dant on combined cisplatin/etoposide therapy cancels a pre-existing protect ive antitumor immune response (presumably cytotoxic-T-cell-mediated) for wh ich the nuclear and cytoplasmic paraneoplastic IgG autoantibodies serve as a surrogate marker. Testing of this hypothesis would require the survival o f seropositive and seronegative patients to be compared in a larger trial, using a therapeutic modality that does not compromise immunocompetence.