A phase I/II study of combined weekly systemic cisplatin and locoregional hyperthermia in patients with previously irradiated recurrent carcinoma of the uterine cervix

Abstract

SummaryWe investigated the feasibility and the anti-tumour activity of weekly cisplatin and the simultaneous application of local hyperthermia in patients with a pelvic recurrence of cervical cancer in previously irradiated area. Dose levels of cisplatin 60 mg m -2 , 70 mg m -2 and 80 mg m -2 were studied. Treatment objective of hyperthermia was the achievement of a tumour temperature of ≥ 42°for 60 min, during cisplatin administration. The protocol advised six weekly cycles of combined treatment. Nineteen patients, median age 47 years (range 26-71), were treated. A total of 89 cycles of combined treatment were administered. Even at the highest dose level of cisplatin, 80 mg m -2 weekly, no dose-limiting toxicity was observed. Leucocytopenia at scheduled retreatment resulted in 1 or 2 weeks postponement in five cases. Neurotoxicity and renal toxicity were mild or absent. Maximum tumour temperatures achieved ranged 39.7-43.6°C, mean 41.6 ± 0.7°C. All 19 patients were evaluable for response. One patient achieved a complete response that lasted 20 months, and nine patients achieved a partial response for a median duration of 6 months (range 4-50+ months), for an overall response rate of 53%. One patient subsequently underwent salvage surgery and currently remains free of disease at 4 years. We found that this combined hyperthermiadose-intensive cisplatin regimen was well-tolerated. The true impact of the combination of cisplatin and locoregional hyperthermia can only be answered in a randomized study. Nonetheless, based on existing data on the poor efficacy of cisplatin in pelvic recurrent cervical cancer, we believe that the combined modality approach of weekly hyperthermia plus dose-intensive cisplatin is an attractive regimen, particularly if subsequent salvage surgery is available.

Treatment outcome analysis of chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone for recurrent cervical cancer, following irradiation

“…Cisplatin has emerged as the most active single agent for treating patients with metastatic disease, and no other standard cytotoxic drug has been consistently associated with objective response rates of ≥25%. However, for patients who experience relapse following definitive radiation therapy, cisplatin has only a minor effect ( 6 , 28 ).…”

“…The recurrence rate is lower for patients with a pelvic recurrence within previously irradiated areas than for those with extra-pelvic sites of disease. In addition, the responsiveness of pelvic recurrences is partial at best and has a brief (median 4–6 months) duration ( 6 ). To enhance the therapeutic response, chemotherapy was combined with hyperthermia (cisplatin + hyperthermia for previously radiated cases), which has been demonstrated to be feasible ( 7 ) when used in tri-modal applications for the cervix ( 8 – 11 ).…”

Effects of hyperthermia on DNA repair pathways: one treatment to inhibit them all

“…Results showed that this form of trimodality treatment is feasible and effective with only moderate toxicity. Also, multiple studies in recurrent cervical cancer show that hyperthermia enhanced the uptake and cytotoxicity of cisplatin without additional side effects [ 19 , 179 – 181 ]. Summarizing, hyperthermia has shown very significant enhancement of the effectivity of both radiotherapy and chemotherapy without increasing toxicity in various multi-modality settings.…”

Hyperthermia in Cancer Care: A Literature Review

“…Two systematic reviews with meta-analysis 7,8 (reporting on seven RCTs), five publications on three RCTs, 19,20,28,29,33 and six singlearm trials were included. [34][35][36][37][38][39] The latest systematic review, which performed two separate analyses (conventional and network meta-analysis) of LRHT for Three controlled trials yielded five publications since the last systematic review. 19,20,28,29,33 One multicentre RCT (n = 101) that included treatment-naive patients with locally advanced cervical cancer reported that the addition of LRHT to CRT did not improve overall five-year survival (adjusted hazard ratio [HR]: 0.485, 95% CI: 0.217-1.082, p = 0.077), disease-free survival (DFS) (adjusted HR: 0.517, 95% CI: 0.251-1.065, p = 0.073), local relapse-free survival (LRFS) (p > 0.05) or CR (p > 0.05) compared with CRT alone.…”