Concurrent chemotherapy, hyperthermia and radiotherapy improve reoxygenation in locally advanced breast cancer

Purpose/Objective: Tumor hypoxia has long been associated with radiation resistance. It also affects drug resistance, angiogenesis, cytokine production, cell cycle control, apoptosis and development of distant metastases. Changing tumor hypoxia could significantly influence tumor treatment response. The objective of this study was to evaluate changes in tumor oxygenation in patients with locally advanced breast cancer (LABC) treated with concurrent taxol, hyperthermia (HT), and radiation (RT). Materials/Methods: Eighteen patients with LABC were enrolled from 10/95 through 2/99. The median age was 52 (range 41 – 66). Taxol (175 mg/m2) was given every three weeks for 3 cycles. RT consisted of 50 Gy, at 2 Gy/day, followed by a boost to 60 to 65 Gy for those not undergoing surgery. Mastectomy was performed for patients deemed resectable after this neoadjuvant program. Following mastectomy, patients without distant metastases received adjuvant Cytoxan, Adriamycin, and 5 Fluorouracil (CAF). HT was administered twice per week with microwave applicators within 30 minutes following RT. The thermal goal was to reach cumulative equivalent minutes at 43°C for 90% of the measured points (CEM 43°T90) of =10 minutes. Oxygenation was measured during RT prior to the first HT treatment and 24 hours following the first HT treatment using a polaragraphic electrode (Eppendorf). Results: Fourteen of 18 patients responded, six with a clinical complete response (CR), nine with a partial clinical response and three were non-responders (NR). Thirteen underwent mastectomy with three pathologic CR. Five of 13 patients had delayed wound healing following mastectomy. The thermal goal was achieved in 10 of 18 patients. There was an inverse correlation between thermal parameters and treatment response. Prior to treatment, tumor oxygenation was measured in 13 out of 18 patients with an average median ± SEM pO2 of 13.5 ± 4.3 mmHg. Tumor hypoxia (median ± pO2 < 10 mmHg) was present in 8/13 patients (average median ± SEM pO2 = 4.7 ± 1.2 mmHg). Five patients had well oxygenated tumors (average median ± SEM pO2 of 27.6 ± 7.8 mmHg). In patients with hypoxic tumors prior to treatment there was a significant improvement (p=0.0002) in tumor pO2 after treatment (average median ± SEM pO2 increased to 23.3 ± 7.7 mmHg). Patients with well-oxygenated tumors prior to treatment as well as those with significant reoxygenation had a favorable clinical response. Improvement in tumor reoxygenation after thermochemoradiotherapy appears to be temperature dependent and associated with relatively low thermal doses. Conclusions: The results of this study suggest that the changes in tumor oxygenation are temperature dependent and that this relationship could possibly influence treatment outcome. It is also likely that at lower thermal doses (which are easily achievable in clinic) tumor reoxygenation is more relevant for tumor response than cytotoxic effect itself. This could be particularly important for thermochemoradiotherapy protocols that include chemotherapeutic agents which activity is known to be oxygen dependent. However, considering limitations due to the small number of patients in this study, it is important to conduct more clinical studies in which thermal parameters and oxygenation are measured to establish more precisely the thermal dose-reoxygenation-response relationship.