Longitudinal NSCLC Treatment Progression via Multimodal Generative Models

Lung cancer remains the leading cause of cancer-related mortality worldwide, with survival outcomes critically dependent on early and accurate detection. When low-dose computed tomography (LDCT) findings are indeterminate, clinicians typically defer diagnosis pending follow-up CT imaging obtained up to 12 months later, inevitably delaying treatment for patients with malignant nodules. To address this clinical gap, we propose Nodule-Aligned Multimodal (Latent) Diffusion (NAMD), a novel generative framework that synthesizes one-year follow-up nodule CT images conditioned on the baseline CT scan, quantitative nodule biomarkers, and patient-level Electronic Health Records (EHR), enabling timely prediction of nodule malignant progression without requiring actual follow-up scans. NAMD introduces two key contributions: (i) a nodule-aligned latent space regularized so that embedding distances reflect clinically meaningful biomarker changes, and (ii) an LLM-driven multimodal conditioning mechanism encoding heterogeneous EHR data into the diffusion backbone. Evaluated on the National Lung Screening Trial (NLST), our method's synthetic follow-up images achieve an AUROC of 0.805 and an AUPRC of 0.346 for lung nodule malignancy prediction, outperforming both the baseline LDCT performance without virtual follow-up generation, and existing state-of-the-art conditional generation methods, while maintaining competitive image quality. These findings suggest that NAMD enables earlier and more accurate lung cancer diagnosis by capturing clinically meaningful features of nodule progression.

Lung cancer results in roughly 1.8 million fatalities annually worldwide, with non-small cell lung cancer (NSCLC) comprising the majority of cases. Despite advancements in treatment, survival stratification remains challenging due to intratumoral heterogeneity inadequately captured by conventional descriptors. Standard radiomic and deep learning techniques regard imaging features as independent quantities, overlooking structured interactions between tumor characteristics. We evaluate whether structured proxy features can enhance multimodal NSCLC survival prediction by augmenting pretreatment computed tomography (CT) representations, radiomics, and clinical variables with six simulation-derived features designed to capture interactions between heterogeneity and morphology. A radiomic-parameterized cellular automaton generates growth-rate and necrosis-ratio proxy features from baseline CT by using entropy and sphericity to compute low-dimensional proxy parameters. The imaging backbone is a Transformer-based Masked Autoencoder (TMAE), which was chosen after a systematic evaluation with alternative encoders within the same pipeline and provides attention-based visualizations that highlight tumor regions receiving higher model attention. On the public Lung1 cohort (n = 390), the primary four-modality fusion attained a C-index of 0.641 (iAUC 0.731, log-rank p < 0.001). The primary result compares favorably with prior multimodal results on Lung1 (C-index 0.631; iAUC 0.592 [15]) under a comparable evaluation protocol, while a separate exploratory coefficient-optimization analysis achieved a best observed C-index of 0.662 (iAUC 0.748). These results indicate that, in addition to conventional radiomic, deep, and clinical representations within the Lung1 benchmark, simulation-derived proxy features may provide complementary predictive information within this fixed Lung1 benchmark.

Zero-shot vision-language models (VLMs) offer a promptable alternative to task-specific training for gross tumor volume (GTV) delineation in non-small-cell lung cancer (NSCLC), but the prompt dimensions that govern their spatial behavior remain poorly understood. We study this question by probing alignment directions in VoxTell on a held-out internal NSCLC tumor dataset through sub-prompt decomposition into diagnosis, demographic, staging, anatomical, generic, and irrelevant controls; attribute-wise perturbation robustness; specificity ladders; and cross-case prompt swaps, while benchmarking against fine-tuned and zero-shot baselines using the Dice Similarity Coefficient (DSC) with Wilcoxon signed-rank tests and Benjamini-Hochberg correction. Alignment analyses revealed that anatomical location is the dominant driver of VoxTell's spatial attention: 63.4 percent of location perturbations caused catastrophic drops, prompt specificity improved from generic to full descriptions except for diagnosis-only prompts, irrelevant prompts correctly yielded zero segmentation, and cross-case prompt swaps confirmed patient-specific conditioning (matched DSC 0.906 vs. mismatched 0.406). Histology and stage substitutions had minimal effect, indicating that the model prioritizes "where to look" over "what to look for." In this context, VoxTell, operating fully zero-shot, achieved a mean DSC of 0.613, statistically indistinguishable from nnUNet (0.690, adjusted p = 0.156) and Ahmed et al. (0.675, adjusted p = 0.679), while significantly outperforming all other zero-shot models. Together, these findings argue that segmentation VLMs should be evaluated not only by Dice, but also by the prompt dimensions to which they align.