Proton Irradiation with Hyperthermia in Unresectable Soft Tissue Sarcoma

Abstract

Purpose: Unresectable soft tissue sarcomas (STSs) do not usually exhibit significant tumor downstaging with preoperative radiotherapy and/or chemotherapy due to their limited radiosensitivity/chemosensitivity. Limb amputations for tumors of the extremities inevitably lead to considerable loss of function and impairment in quality of life. Local hyperthermia at 39°C to 43°C and proton irradiation combine thermoradiobiological and physical dose distribution advantages, possibly mimicking those of a 12C ion therapy. We report the first 2 patients treated with this unique approach of proton thermoradiotherapy.

Materials and methods: Both patients had an unresectable STS of the left lower leg (1 grade 2 myxoid fibrosarcoma, 1 grade 3 undifferentiated pleomorphic sarcoma). Both patients had declined the above-knee amputation that had been advised due to their involvement of the neurovascular bundles. They were, therefore recruited to the Hyperthermia and Proton Therapy in Unresectable Soft Tissue Sarcoma (HYPROSAR) study protocol (ClinicalTrials.gov NCT01904565). Local hyperthermia was delivered using radiofrequency waves at 100 Mhz once a week after proton therapy. Proton irradiation was undertaken to a dose of 70 to 72 Gy (relative biological effectiveness) delivered at 2.0 Gy (relative biological effectiveness)/ fraction daily for 7 weeks.

Results: Patients tolerated the treatment well with no significant acute or late morbidity. Both primary tumors showed a near complete response on serial magnetic resonance imaging. At a follow-up of 5 and 14 months, the patients were able to carry out indoor and outdoor activities with normal limb function.

Conclusion: This is the first report of proton beam irradiation combined with hyperthermia for cancer therapy. Our first experience in 2 consecutive patients with unresectable STSs shows that the approach is safe, feasible, and effective, achieving functional limb preservation with near total tumor control.

Keywords: hyperthermia; proton therapy; radiation therapy; soft tissue sarcoma; unresectable.

Conflict of interest statement

Conflicts of interest: None of the authors has any conflict of interest to be declared.

© Copyright 2016 International Journal of Particle Therapy.

Figures

Figure 1.

Summary of the Hyperthermia and Proton Therapy in Unresectable Soft Tissue Sarcoma (HYPROSAR) study protocol.

Figure 2.

Patient 1. Myxofibrosarcoma of the left lower leg (indicated by white arrows) at presentation before surgery, measuring 11.1 × 7.4 × 4.3 cm3 (maximum diameter) in the flexor musculature of the left lower leg on coronal and (A) axial (B) contrast-enhanced fat-suppressed T1-weighted magnetic resonance imaging. The periarticular tumor extended to the knee joint and showed inhomogeneous contrast medium enhancement with encasement of the popliteal artery and peroneal nerve. (C, D) Post-biopsy scans taken 3 months after partial tumor resection and before proton thermoradiotherapy demonstrated tumor debulking (8.5 × 3 × 4.4 cm3) with homogeneous enhancement and tumor extension to the knee. (E, F) Magnetic resonance imaging after 4 weeks of proton and hyperthermia therapy revealed a slight increase in tumor size (9.8 × 2.9 × 4 cm3) but visible reduction of contrast enhancement. (G, H) Magnetic resonance imaging 7 weeks after completion of proton thermoradiotherapy shows a small residual tumor with minimal periarticular contrast enhancement dorsal to the knee joint. (I, J) Four months after completion of treatment, liquefaction with very subtle residual rim enhancement without new nodular tumor enhancement could be observed. (K, L) Ten months later, no further significant changes were observed.

Figure 3.

Patient 1 with myxoid fibrosarcoma of the left lower leg treated with hyperthermia and proton therapy. (A) Hyperthermia treatment plan: 95% of the tumor volume received a temperature of 39°C, 70% received a temperature of 41.5°C while 56% of the volume had a temperature of at least 43°C as evident in the thermal dose-volume histogram. The maximum intratumoral temperature was estimated as 52°C. (B) Proton therapy plan for planning target volume 1 (clinical target volume 1 plus 7 mm) including tumor and muscle compartment with safety margins: 64 Gy (RBE), 2 Gy (RBE) per fraction, 2 lateral fields per treatment plan. Not shown: boost plan with additional 6 Gy (RBE). Abbreviation: RBE, relative biological effectiveness

Figure 4.

Patient 1 with myxoid fibrosarcoma of the left lower leg treated with (A) hyperthermia at Kantonsspital, Aarau, Switzerland, and (B) proton beam therapy at Paul Scherrer Institute, Villigen, Switzerland.

Figure 5.

Patient 2 with undifferentiated pleomorphic sarcoma of the left lower leg (indicated by white arrows) at presentation, measuring 4 × 2.3 × 5.2 cm3 in the flexor musculature of the left lower leg on (A) sagittal short T1 inversion recovery magnetic resonance image and (B) axial contrast-enhanced fat-suppressed T1-weighted magnetic resonance imaging. (C, D) Post-biopsy magnetic resonance image scans at the time of proton beam and hyperthermia planning demonstrated tumor progression (5.1 × 3.9 × 7.5 cm3) with inhomogeneous enhancement and increasing edema of adjacent musculature. (E, F) Magnetic resonance image after 4 weeks of proton and hyperthermia therapy revealed a slight increase in tumor size with reduction of contrast media uptake. (G, H) The progressive perifocal edema might be a consequence of irradiation. Follow-up magnetic resonance image at 6 weeks after therapy shows both reduction in tumor size and perifocal edema. The tumor shows post-therapy changes with liquefaction and only very subtle residual rim enhancement without nodular tumor enhancement. (I) Tumor regression continued at 20 weeks after completion of therapy with no significant differences concerning signal intensity on coronal short T1 inversion recovery technique. No new nodular enhancement was seen on dynamic contrast enhanced images acquired after contrast administration at (J, K) 5 minutes, (L) 10 minutes, and (M) 15 minutes.

Figure 6.

Patient 2 with undifferentiated pleomorphic sarcoma of the left lower leg treated with hyperthermia and proton therapy. (A) Hyperthermia treatment plan with the color map of the temperature distributions along the target volume (upper row, inserts 1 to 3). The cumulative temperature-volume histogram (last insert in the upper panel) shows that 95% of the tumor volume received a temperature of 39°C, 70% received a temperature of 41.5%, and 56% of the volume had a temperature of at least 43°C with a maximum intratumoral temperature of 45°C. (B) Proton therapy summary plan with 2 lateral fields per treatment plan prescribed for 2 Gy (RBE) per fraction. Planning target volume 1 (clinical target volume 1 plus 7 mm; outer green line) including tumor and muscle compartment with safety margins: total dose 60 Gy (RBE). Boost planning target volume 2 (clinical target volume 2 plus 7 mm; inner green line): total dose 12 Gy (RBE). The distribution of the proton dose profiles along the target volume is depicted (last insert in the lower panel). Abbreviation: RBE, relative biological effectiveness