Clinical Evidence by Indication

Pediatric soft tissue sarcomas (STS) is a heterogeneous group of malignant tumors that account for 7% of all childhood tumors. Fortunately, cancer in children and adolescents is rare, although incidents have been increasing since 1975.

Clinical results like the ones below reveal that Chemotherapy treatments are more effective when combined with Hyperthermia. Hyperthermia warms the tumor to temperatures in the "fever range" which makes the cancer cells more sensitive to treatment. Normal healthy cells recover while cancer cells die.

Treatment Modality:

Hyperthermia in addition to chemotherapy was investigated as second line treatment in children with soft tissue sarcomas, and in children with refractory or recurrent germ cell tumors. Chemotherapy consisted of VP16 100 mg/m2,  ifosfamide 2000 mg/m2, and CDDP 40 mg/m2, delivered over 4 days. Hyperthermia was applied on the 1st and 4th day.

Clinical Results

In soft tissue sarcoma the combined treatment resulted in 40% 3-7 years overall survival

In germ cell tumors the combined  treatment resulted in a high overall survival, especially in children who were treated for a refractory tumor or a first relapse

Treatment Modality:

In patients with a first relapse, the results of children treated with the combination were compared to those in matched controls treated with chemotherapy alone, which data were available from the Registry of the German Society for Pediatric Oncology & Hematology. Five-year overall survival was 38% for children treated with chemotherapy alone, while it was 93% for children treated with chemotherapy and hyperthermia. BSD-2000 and BSD-2000/3D/MR used in Düsseldorf UMC site.

Endorsement:

Additional hyperthermia is considered standard of care for children with a recurrent sarcoma or germ cell tumor by the German Society for Pediatric Oncology & Hematology.

References:

• Wessalowski et al. Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single institution, phase 2 study. Lancet Oncology 2013 July 1 (online).
• Wessalowski et al. An approach for cure: PEI-chemotherapy and regional deep hyperthermia in children and adolescents with unresectable malignant tumors. Klin Padiatr. 2003 Nov-Dec;215(6):303-9.
• Schneider et al. Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96. J Clin Oncol. 2001 Apr 1;19(7):1951-60.

Colorectal cancer is the third most common cancer in world according to the World Cancer Research Fund International. With nearly 1.4 million new cases diagnosed in 2012. New evidence shows that, in many cases, diet and exercise can prevent the disease.

Clinical results like the one below reveal that Radiation treatments are more effective when combined with Hyperthermia. Hyperthermia warms the tumor to temperatures in the "fever range" which makes the cancer cells more sensitive to treatment. Normal healthy cells recover while cancer cells die.

Clinical Evidence

7a. Rectal Cancer

A Cochrane review was performed to quantify the potential beneficial effect of hyperthermia in addition to radio(chemo) therapy in locally advanced rectal cancer. Six randomized trials were included.

Clinical Results

A significant higher complete response rate was observed in the combined treatment arms (RR 2.67, p=0.01). Overall survival after 2 years was significantly higher in the combined treatment arm (OR 0.49, p= 0.001), although this difference disappeared at longer follow-up times.

Reference:

De Haas-Kock et al. Concomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer. Cochrane Database of Systematic Reviews 2009, issue 3.

7b. Rectal cancer palliative treatment

One randomized trial compared conventional radiotherapy with or without hyperthermia in patients with rectal cancer. In another study the palliative effect of reirradiation plus hyperthermia was evaluated.

Results

In the randomized trial the palliative effect of radiotherapy combined with hyperthermia was larger than that of radiotherapy alone. With hyperthermia, complete palliation was achieved in 45% of the patients for a median duration of 17 months, vs 25% for a median duration of 7 months without hyperthermia.

Reirradiation with 8 fractions of 4 Gy, applied twice weekly, combined with hyperthermia, resulted in a good or complete palliation in 72% of the patients, for a median duration of 6 months.

The Dutch Deep Hyperthermia Trial has recruited patient at AMC Amsterdam and Erasmus Rotterdam; Amsterdam has used its home build device similar to the BSD 1000 and Rotterdam the BSD 2000 device.

Juffermanns has been using a third party device to be identified in the publication.

Hyperthermia and Radiotherapy:

When hyperthermia is combined with radiotherapy, general treatment guidelines of the ESHO European Society of Hyperthermic Oncology recommend:

• Target volume for hyperthermia: When the radiotherapy total dose is considered to be sufficient for a high probability of local control for microscopic disease, the target volume for hyperthermia is the gross tumor volume. When the radiotherapy total dose is lower, the target volume for hyperthermia is the clinical target volume.
• Sequence of treatment modalities: Hyperthermia is given after the radiotherapy fraction, once or twice weekly with a time interval between two hyperthermia treatments of minimum 72 hours. The time interval between radiotherapy and hyperthermia may vary from 30 minutes to five hours.
• Duration of hyperthermia treatment: Superficial hyperthermia total 60 minutes, deep hyperthermia total 90 minutes (including 30 minutes heating-up time)

Endorsement:

Reirradiation and hyperthermia is considered standard of care by the Health Insurance Council of the Netherlands.

References:

• Van der Zee and González González. Authors reply. The Lancet 2000;356:772.
• Juffermans et al. Reirradiation and hyperthermia in rectal carcinoma: a retrospective study on palliative effect. Cancer. 2003 Oct 15;98(8):1759-66.

Clinical results like the one below reveal that Chemotherapy treatment is more effective when combined with Hyperthermia. Hyperthermia warms the tumor to temperatures in the "fever range" which makes the cancer cells more sensitive to treatment. Normal healthy cells recover while cancer cells die.

Clinical Evidence

Tumor Entity:

Soft tissue sarcoma primary or locally recurrent both of the trunk and the extremities.

Treatment Modality:

Primary or locally recurrent soft tissue sarcoma,  both of the trunk and the extremities, were treated with 4 cycles of chemotherapy, Etoposide, Iphosphamide and Adriamycin, both pre and post local treatment.  Patients were randomized to additional hyperthermia or not. All contributing centers have been using the BSD-2000 and BSD-2000-3D devices.

Disease Free Survival after 7 years (Issels 2010)

• Chemotherapy EIA alone: 21%
• Chemotherapy EIA plus Hyperthermia: 42%

Endorsements:

• ESMO European Society of Medical Oncology – level I, Europe
• NCCN National Cancer Center Network Treatment Guidelines – level 1B, USA

Chemotherapy and Hyperthermia:

When hyperthermia is combined with chemotherapy, general treatment guidelines of the ESHO European Society of Hyperthermic Oncology recommend:

• Target volume for hyperthermia: The target volume for hyperthermia is the gross tumor volume.
• Sequence of treatment modalities: Hyperthermia is given simultaneously with chemotherapy during cytostasis.
• Duration of hyperthermia treatment: Superficial hyperthermia total 60 minutes, deep hyperthermia total 90 minutes (including 30 minutes heating-up time)

References:

• R.D.Issels et al. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010 Jun;11(6):561-70.
• Issels RD. Regional hyperthermia in high-risk soft tissue sarcomas. Curr Opin Oncol. 2008 Jul;20(4):438-43.
• Issels et al. Regional hyperthermia (RHT) improves response and survival when combined with systemic chemotherapy in the management of locally advanced, high grade soft tissue sarcomas (STS) of the extremities, the body wall and the abdomen: A phase III randomised prospective trial (EORTC/ESHO intergroup trial). J Clin Oncol.. 2007; Volume 25, Issue 18S-June 20.
• Wendtner et al. Response to neoadjuvant chemotherapy combined with regional hyperthermia predicts longterm survival for adult patients with retroperitoneal and visceral high-risk soft tissue sarcomas. J Clin Oncol. 2002 Jul 15;20(14):3156-64.
• ESMO / European Sarcoma Network Working Group: Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 Oct;23 Suppl 7:vii92-9.
• NCCN Clinical Practice Guidelines in Oncology™ Soft Tissue Sarcoma, Version 2.2011

Anal cancer is diagnosed in over 30,000 people worldwide each year, according to the World Cancer Research Fund International. An estimated 90% were attributable to Human papillomavirus (HPV).

Clinical results like the one below reveal that both Chemotherapy and Radiation treatment are more effective when combined with Hyperthermia. Hyperthermia warms the tumor to temperatures in the "fever range" which makes the cancer cells more sensitive to treatment. Normal healthy cells recover while cancer cells die.

Clinical Evidence

Treatment Modality:

Patients with T2 and T3 anal carcinomas were randomized to treatment with radiotherapy, 55 Gy, and chemotherapy, 5-FU and mitomycin-C,  with or without hyperthermia.

Clinical Results:

96% of the patients in the treatment arm with hyperthermia and 68% in the treatment arm without hyperthermia had preserved their anorectal function 5 years after treatment. Both local recurrence free survival and disease specific survival was significantly higher in the patient group treated with hyperthermia. Study used a third party hyperthermia device.

• Preserved function after 5 years without Hyperthermia: 68 %
• Preserved function after 5 years with Hyperthermia: 96 %

Kaplan Meier curve showing the disease specific survival time stratified per randomized arm for a five year follow-up.

Hyperthermia and Chemotherapy:

When hyperthermia is combined with chemotherapy, general treatment guidelines of the ESHO European Society of Hyperthermic Oncology recommend:

• Target volume for hyperthermia: The target volume for hyperthermia is the gross tumor volume.
• Sequence of treatment modalities: Hyperthermia is given simultaneously with chemotherapy during cytostasis.
• Duration of hyperthermia treatment: Superficial hyperthermia total 60 minutes, deep hyperthermia total 90 minutes (including 30 minutes heating-up time) ) at temperatures of 40 to 44 °C in the whole target volume

References:

• Kouloulias et al. Chemotherapy combined with intracavitory hyperthermia for anal cancer. Feasibility and long-term results from a phase II randomized trial. Am J Clin Oncol 2005;28:91-99