We hypothesized, that tumor systems-directed therapies might have the capability to therapeutically modulate and redirect the tumor systems’ stability, homeostasis, robustness, and normative notions. This therapeutic ‘top down’ strategy may provide novel targets for the control of metastatic tumor disease. We comparatively analyzed redirection and modulation of tumor-associated normative notions, particularly inflammatory, osteoblastic activities, ECOG status, and metastatic potential in parallel with response, time to response and duration of response induced by continuously administered biomodulatory treatment modules (module M: metronomic low-dose chemotherapy; module A: pioglitazone plus etoricoxib; module A+M; module A+M/+: plus second transcriptional modulator [interferon-alpha or dexamethasone +/− imatinib or dexamethasone plus lenalidomide]) in the metastatic stages of seven different histological tumor types (ten phase II trials, two of them randomized; 333 patients; 80 % systemically pre-treated). A series of (randomized) phase II studies demonstrated differentially modularized accessibility of tumor-associated normative notions, i.e., inflammation, ECOG status, osteoblastic metastases, and metastatic tumor spread for mediating objective tumor response. Biomodulatory treatment schedules may induce long-term disease stabilization followed by prolonged objective response (3–100 %), even continuous complete remission, despite poor or no monoactivity of the respective drugs. Progression-free survival data are comparable with those of reductionist-designed standard first-line therapies. The differential response patterns indicate the therapies’ systems biological activity. Clinical efficacy of ‘top-down’ therapy strategies (biomodulatory therapy elements administered as fixed modules) for metastatic cancer provide excellent opportunities to point to central problems of communication among ‘systems participators’ in tumors. Combined modularized therapies (1) help to detect multifaceted, situatively adapted rationalization processes available for ubiquitously occurring tumor-immanent normative notions, (2) may uncover novel regulatory systems in tumor biology (e.g., hubs), (3) pathologies within communication processes (e.g., inconsistencies, disturbances in intersystemic exchange processes) (4) are a basis for studying communicative rules mediating the ‘metabolism’ of tumor evolution, and (5) may pave the way for inducing biological memory in metastatic tumors.