Clinical Evidence by Indication

Highlight of several hyperthermia clinical studies organized by indication

Breast cancer is the most common cancer in women worldwide according to the World Cancer Research Fund International. With nearly 1.7 million new cases diagnosed in 2012 (second most common cancer overall). This represents about 12% of all new cancer cases and 25% of all cancers in women.

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

Tumor Entity:

Results of five randomized controlled trials on radiation with or without hyperthermia in advanced or recurrent breast cancer were combined in one analysis.

Treatment Modality:

Radiotherapy, dose and scheme depending on previous irradiation or not, and varying per trial. Superficial hyperthermia was applied once or twice weekly.

Clinical Results:

The combination of results in total 306 patients showed a significant improvement in complete response rate in the group treated with radiotherapy and hyperthermia: 59% vs 41%. This initial improvement in local tumor control was maintained during follow-up. In one of the trials (ESHO), all patients were treated after previous irradiation and reirradiated with 8 fractions of 4 Gy, two fractions per week. The difference in local tumor control between the two treatment arms was significant and remarkably high in this subgroup: CR rate was 39% without hyperthermia, and 79% with hyperthermia, with similar differences in local tumor control during follow-up. Not all trials cited used the BSD-500 specifically.

Evidence Level I Randomized Clinical Trial Results on 306 Patients (Vernon et al.):

  • Complete Remission Rate without Hyperthermia: 41 %
  • Complete Remission Rate with Hyperthermia: 59 %

breast ht graph

Subgroup after previous irradiation and reirradiated (ESHO):

  • Complete Remission Rate without Hyperthermia: 39 %
  • Complete Remission Rate with Hyperthermia: 79 %

 breast ht 2 graph

Endorsements:

The combination of Radiotherapy and Hyperthermia is the treatment of choice for Breast Cancer (Level I Evidence) recommended by

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 maximally 90 minutes (including up to 30 minutes heating-up time) at temperatures of 40 to 44 °C in the whole target volume.

References:

Cervical cancer is the fourth most common cancer affecting women worldwide according to the World Health Organization. With nearly 528,000 new cases diagnosed every year. It is also the fourth most common cause of cancer death (266,000 deaths in 2012) in women worldwide.

Level 1 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

Tumor Entity:

A Cochrane review was performed to investigate whether adding hyperthermia to standard radiotherapy or chemoradiation for locally advanced cervical cancer has an impact on local tumor control, survival, and treatment related morbidity. The review included six randomized trials in patients with primary cervical cancer stage IIB, IIIB and IV.

Treatment Modality:

Conventional external beam radiotherapy and brachytherapy, in one trial with chemotherapy as well. Patients were randomized for additional hyperthermia, 3-12 treatments in the period of external radiotherapy.Patients recruitment sites: AMC Amsterdam using a device similar to the earlier designed BSD-1000, Erasmus MC Rotterdam used the BSD-2000 Hyperthermia device.

Clinical Results:

The majority of patients (74%) included in the studies had FIGO stage IIIB cervical carcinoma. Overall, treatment outcome was significantly better for patients receiving the combined treatment. The pooled data analysis yielded a significantly higher complete response rate (RR 0.56; 95% CI 0.39-0.79; p<0.001), reduced local recurrence rate at 3 years (HR 0.48; 95% CI 0.37-0.63; p<0.001), and better overall survival at 3 years (HR 0.67; 95% CI 0.45-0.99; p=0.05) after combined treatment. No significant difference was observed in treatment related acute (RR 0.99; 95% CI 0.30-3.31; p=0.99) or late grade 3-4 toxicity (RR 1.01; 95% CI 0.44-2.30; p=0.96) between the two treatment arms.

From one of these randomized trials long-term results have been published, showing a significant better overall survival up to 12 years after radiotherapy plus hyperthermia.

  • 12 year Overall Survival with Radiotherapy alone 20%
  • 12 year Overall Survival with Radiotherapy plus Hyperthermia 40%

cervical graphEndorsements:

These bodies recommend Radiotherapy and Hyperthermia as a combination therapy for cervical cancer:

  • The Health Insurance Council of the Netherlands
  • FDA US Food & Drug Administration: Patients with advanced disease not apt for chemotherapy; HDE Humanitarian Device Exemption
  • Integrated Cancer Center of the Netherlands - Guidelines for oncological care

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)

References:

Esophageal (Oesophageal) cancer is the eighth most common cancer worldwide according to the World Cancer Research Fund International. With nearly 456,000 new cases diagnosed in 2012. About 75% of those cases are diagnosed in Asia.

Level 1 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

Tumor Entity:

Primary thoracic esophageal cancer stage III and IV

Treatment Modality:

Three randomized studies were performed in esophageal cancer, comparing radio and/or chemotherapy with or without intraluminal hyperthermia. Kitamura et al. compared preoperative radiochemotherapy with or without hyperthermia. Wang et al. compared 60 Gy alone to 40 Gy plus hyperthermia. Sugimachi et al. compared preoperative chemotherapy with or without hyperthermia. Third party hyperthermia devices used.

esophagus ht table

Clinical Results:

  • Kitamura et al. found a significantly higher pCR in the plus hyperthermia treatment arm: 25% vs 6%.
  • Wang et al. found a significantly better 3-y overall survival with hyperthermia: 42 vs 24%.
  • Sugimachi et al. found that the local effects tended to be better in the plus hyperthermia group: improvement of dysphagia 70% vs 40%; radiographic improvement 50% vs 25%, and histopathological evidence of treatment effect 41% vs 19%.

Duration of hyperthermia treatment

Intraluminal hyperthermia total 30 minutes

References:

Head and Neck cancer is the sixth most common cancer in worldwide according to World Health Organization and the most common cancer in developing countries. With nearly 664,000 new cases annually. Two-thirds of these occurring in developing countries.

Clinical results like the one below reveal that 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

Tumor Entity:

Advanced Head and Neck Tumors with Lymph Node Metastasis

Treatment Modality:

In three trials patients with head and neck tumors were randomized to radio(chemo)therapy with or without hyperthermia. Radiotherapy was applied with 2 Gy fractions up to a total dose of 66-70 Gy. Chemotherapy was only applied in the study by Hua et al., to patients with T3-T4 tumors only. Hyperthermia was given once or twice weekly Valdagni, Trento Italy study used BSD-1000.  

Clinical Results:

All three studies showed a significant improvement in complete response rate, and higher local tumor control and overall survival rates, or a longer median survival, when radio(chemo)therapy was combined with hyperthermia.

  RT alone RT plus Hyperthermia
  CR LC OS CR LC OS
Valdagni 41% 5-y 24% 5-y 0% 83% 5-y 69% 5-y 53%
Hua 81% 5-y 79% 5-y 70% 95% 5-y 91% 5-y 78%
Huilgol 42% not reported median 0.40 y 79% not reported median 0.66 y

 

  • 41 pts, 44 nodes. Radiotherapy 64-70 GY, 5 fractions/week of 2-2.5 Gy
  • Complete Remission Rate without Hyperthermia: 41 %
  • Complete Remission Rate with Hyperthermia: 83 %
  • 5yr nodal control RT - 24%; RT+HT - 69%
  • 5yr overall survival RT - 0% RT+HT - 53%
  • No enhancement of acute or late toxicity

Endorsements:

The combination of Radiotherapy and Hyperthermia is the treatment of choice for Head & Neck Cancer (Level I Evidence) recommended by

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: