The OtR tumor recurrence and metastasis model reveals doxorubicin‐induced tumor shrinkage doesn't guarantee prolonged survival

BACKGROUND: In preclinical research, tumor growth inhibition in subcutaneous models is frequently employed to evaluate therapeutic efficacy; however, such models often lack clinical translatability. METHODS: To better approximate clinical reality, taking the case of doxorubicin treatment, we utilized an orthotopic transplant and resection (OtR) strategy to systematically assess the effects of neoadjuvant chemotherapy, adjuvant chemotherapy, and their combination on tumor growth, recurrence, and malignant progression. RESULTS: Surprisingly, none of the treatments improved mouse survival, with adjuvant therapy even shortening it. Although neoadjuvant chemotherapy delayed preoperative tumor growth, and all regimens reduced recurrence rates, none effectively prevented metastasis. Furthermore, all treatment groups exhibited weight loss, indicative of chemotherapy-induced cachexia. CONCLUSIONS: Collectively, these findings demonstrate that reduced tumor growth in preclinical mouse models does not necessarily translate into overall survival benefit. Our results emphasize the critical importance of prioritizing metastasis prevention over tumor growth inhibition as a key efficacy endpoint in antitumor drug evaluation.