Our protocols and projects

ICHS-IT

MODULATED ELECTRO-HYPERTERMIA

(mEHT)

This section contains some schemes of combination chemiotherapy-hyperthermia protocols that were made in collaboration with Italian hyperthermia centers.

They include different types of tumor: gastric, breast, pancreas, lung and describe the day and the duration of the hyperthermia session.

WARNING
Please note that the present schemes must be adapted to the singular case according to patients' characteristics.
The present booklet is not to be considered as an approved guideline.

You can find you detailed protocols in this pubblication:
Fiorentini G, Sarti D, Casadei V, Minnaar C, Szasz MA .Modulated electro-hyperthermia (mEHT) [oncothermia®] protocols as complementary treatment Oncothermia Journal, Volume 25,April 2019 https://oncotherm.com/sites/oncotherm/files/2019-05/FIORENTINI2.pdf

https://igevo.jimdofree.com/hyperthermia-protocols/

A Multicenter, Prospective Clinical Trial of the Clinical Effectiveness of Oncothermia Combined With Standard Chemotherapy in Metastatic Pancreatic Cancer Patients

Aims
Patients with pancreatic cancer often suffer from pain. Because of such a pain, their quality of life have seriously deteriorated. There have been a few studies that showed an effect for pain control by hyperthermia (heating the patient's body). However, there are several limitations in conventional hyperthermia.
In a previous pilot study (NCT02150135), it was found the improvement of quality of life, function, and symptom.
From this background, the investigators tried to show the effect of "Oncothermia" with conventional chemotherapy for pain control, increasing quality of life, and anti-tumor treatment.
Study Arms ICMJE
•Experimental: Oncothermia
EHY-2000 local machine is used for mEHT in the trial.
Modulated Electro-Hyperthermia (mEHT): 120 Watt x 60 min /session with big applicator, diameter=30 cm
Associated to ◦Drug: FOLFIRINOX, GEM-ABRA, GEM-OX, GEMCITABINE
Oxaliplatin 85 mg/m2 in double way with Folic Acid 200 mg/m2, day 1
Irinotecan 165 mg/m2 day 1
5-FU 3200 mg/m2 day 1 for 48 hours
•Active Comparator: Control : FOLFIRINOX, GEM-ABRA, GEM-OX, GEMCITABINE alone

Eligibility Criteria
Inclusion Criteria:
•Patients with pathologically confirmed pancreatic adenocarcinoma
•Patients with radiologically identified metastasis (CT or MRI)
•Patients with no history of previous chemotherapy
•Patients with ECOG score 0-2
Exclusion Criteria:
•Patients who have an experience of hyperthermia treatment

•Patients who have a difficulty of sensing heat

•Patients who have a skin graft or breast reconstruction surgery

•Patients who have a cardiac pacemaker or an implanted metal

•Pregnant or breast feeding women

•Patients with uncontrolled infection, diabetes, hypertension, ischemic heart disease, myocardial infarct within 6 months

•Patients who were treated with unproved drugs within 30 days

•Patients who have a serious disease which can affect the person's safety

•Patients who do not consent to the study

Outcome measures

Outcome Measures

EORTC QLQ-C30 questionnaire score change [ Time Frame: 3 months ]

Secondary Outcome Measures

•change of opioid use amount [ Time Frame: 3 months ]

•change of pain score (VAS score) [ Time Frame: 3 months ]

•Adverse effect [ Time Frame: 3 months ]

Weekly chemotherapy in association with Oncothermia in Patients with Recurrent or Persistent Epithelial Ovarian

Aims
The investigators aimed to evaluate the safety of weekly paclitaxel with oncothermia and weekly paclitaxel with oncothermia in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.
The investigators planned to perform it for 1 year. In this trial, a total of 20 patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma are treated with weekly paclitaxel and oncothermia. Limiting toxicity is evaluated after treating 3 patients for 4-cycles. Primary endpoints are response rate, progression-free survival, overall-survival, quality of life, pain, fatigue and compliance rate. Secondary endpoints: occurrence of limiting toxicity.

Detailed Description
Subjects of study are patients diagnosed as recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. The number of subjects of study is 20 patients. All subjects are treated with weekly paclitaxel 70mg/m2 (IV) on day 1, 8, and 15 at an intervals of 4 weeks. Thermotherapy is performed by applying oncothermia (EHY 2000) probe on the part of body where tumor is located and delivering energy. It is performed on day 1, 4, 8, 11, 15, 18, 21, and 24 (8 times in total every cycle). Oncothermia can be performed a day earlier than scheduled day or a day later than scheduled day. It takes 60 minutes to treat a site for oncothermia. Energy is gradually increased from 60W to 140W. With tumors at multiple sites, oncothermia is performed several times changing sites that apply probe and type of probes. Oncothermia is performed for 60 minutes per each application. Limiting toxicity is evaluated after treating 3 patients for 4-cycles. In group that limiting toxicity occur in the rate equal to or less than 1 patient, limiting toxicity is evaluated after treating 3 additional patients for 4-cycles. When limiting toxicity occur in the rate equal to or less than one of six assessable patients, it is considered that the specific therapy is safe enough to be used in phase 2 trial. . Primary endpoints are response rate, progression-free survival, overall-survival, quality of life, pain, fatigue and compliance rate. Secondary endpoints: occurrence of limiting toxicity.
Patients visit twice a week until 4-cycles are completed or progression of disease is confirmed.
Protocol
•Drug: weekly paclitaxel 4 cycles
Patients are treated with weekly paclitaxel 70mg/m2 (IV) on day 1, 8, and 15 at an intervals of 4 weeks
•Device: oncothermia
Thermotherapy is performed by applying oncothermia (EHY 2000) probe on the part of body where tumor is located and delivering energy. It is performed on day 1, 4, 8, 11, 15, 18, 21, and 24 (8 times in total every cycle). 120 Watt x 60 min /session with big applicator, diameter=30 cm.
Oncothermia can be performed a day earlier than scheduled day or a day later than scheduled day. With tumors at multiple sites, oncothermia is performed several times changing sites that apply probe and type of probes.
Eligibility Criteria ICMJE
Inclusion Criteria:
•Recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma (At the first diagnosis, pathologic findings should be confirmed.)
•Response assessments that are possible by using radiologic tests or tumor markers
•The number of chemotherapeutic regimens that were previously used ≤ 2
•Adequate hematologic, hepatic, and renal functions
•ECOG performance status 0 - 2
Exclusion Criteria:
•Recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma that are located on the part of body where it is impossible to deliver energy by using oncothermia (EHY 2000) probe
•Neurotoxicity ≥ grade 2
•Pacemaker user
•Large metal materials such as artificial joint that are kept in the body
•Recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma that are located on the part of body where got previously radiation therapy
Outcome measures
Current Primary Outcome Measures
•response rate
•progression-free survival
•overall-survival
•quality of life, assessed with the Korean version of WHO Quality of Life-BREF (WHOQOL-BREF
•pain, assessed with the Korean version of the brief pain inventory (BPI).
•fatigue, assessed with the Korean version of the Brief Fatigue Inventory (BFI).
•compliance rate Compliance rate would be assessed with the number of patients that are dropped out from current clinical trial based on other reasons instead of disease. It would be recorded as compliance rate = the number of patients that are dropped out due to other reasons/the number of total patients · 100 (%)

Local Modulated Electro-Hyperthermia in Combination With Intraperitoneal Chemoinfusion in Treatment of Peritoneal Carcinomatosis With Malignant Ascites:

Aims

This trial studies efficacy and safety of combination of modulated electro-hyperthermia (mEHT) with standard chemoinfusion CDDP

Detailed Description

Conservative treatment of peritoneal carcinomatosis with malignant ascites (PCMA) is based on chemoinfusion with its inherent toxicity. There is a strong demand for a safe and non-toxic method of treatment of PCMA. The new technology of modulated electro-hyperthermia (mEHT) has proven efficacy in many advanced cancers with minimal side effects and synergy with Intraperitoneal chemoinfusion (IPCI) with cisplatin that is a widespread standard treatment of PCMA in many countries

Protocol

•Device: Modulated Electro-Hyperthermia (mEHT)

EHY-2000 local machine is used for mEHT in the trial.

Modulated Electro-Hyperthermia (mEHT): 150 Watt x 60 min

•Drug: IPCI (CDDP)

Intraperitoneal chemoinfusion of CDDP (30-60 mg)

IPCI: CDDP (30-60 mg/sqm of body surface), dissolved in 100 mL of normal saline, after abdominal paracentesis and catheterization with following closed drainage of the ascites up to small amount of remaining liquid. After IPCI, the catheter occluded. Administered biweekly during four weeks of the course, totally two times.

Eligibility Criteria

Inclusion Criteria:

•Pathologically confirmed PC with malignant ascites.

•Karnofsky Performance Status (KPS) score ≥60%.

•Normal function of bone marrow.

•Predicted survival time >1 month.

•Written informed consent.

Exclusion Criteria:

•Surgery within 3 weeks or not full recovery of postoperative suture.

•Active bleeding or vascular occlusion in the mEHT treatment area.

•Emotional instability.

•Impossibility to place the patient into the mEHT machine.

•Metallic implants or replacements in the treatment area.

•Electronic implanted devices anywhere.

•Missing or damaged heat-sense nerves or other field-sensitive issues in the treatment area.

•Very low white blood cell count (<1.5×10(9)/L), agranulocytosis (<0.5×10(9)/L) or severe anemia.

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) [ Time Frame: 8 weeks after start of treatment (4 weeks on completion of treatment) ]

Objective Response Rate (ORR) = Complete Remission (CR) + Partial Remission (PR) WHO criteria of therapeutic effect evaluation at malignant ascites: •Complete Remission (CR): complete absorption of ascites with no obvious regeneration for more than 1 month.

•Partial Remission (PR): more than 50% reduction of ascites, with obvious relief of abdominal distention, with maintenance of less than moderate volume of ascites under ultrasound detection for more than 1 month.

•No Change (NC): less than 50% reduction of ascites, or no obvious reduction of ascites under ultrasound detection, or even increase of ascites, with obvious abdominal distention.

Secondary Outcome Measures

•Adverse Events Rate (AER) [ Time Frame: During 4 weeks of treatment course and 4 weeks after treatment]

Common Terminology Criteria for Adverse Events (CTCAE) (v4.03: June 14, 2010) U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES, National Institutes of Health, National Cancer Institute.

•Quality of Life (QoL) [ Time Frame: 8 weeks after start of treatment (4 weeks on completion of treatment)] Karnofsky Performance Score Improvement Rate (KPS IR) ◦Improvement: increase of KPS for ≥10% after treatment. ◦Worsening: reduction of KPS for ≥10% after treatment.◦NC: change of KPS for <10%.

Modulated Electro-Hyperthermia in Combination With metronomic temozolomide in Treatment of brain tumors

Aims

This trial studies efficacy and safety of combination of modulated electro-hyperthermia (mEHT) with metronomic temozolomide (TMZ) in treatment of brain tumors (glioma and astrocytoma), versus best supportive care (BSC).

Detailed Description

There are interesting studies on glioma therapy with modulated electro-hyperthermia (mEHT), which combines the heat-therapy with an electric field. Clinical researchers not only found the mEHT method feasible for palliation but also reported evidence of therapeutic response.

Purpose: To study efficacy and safety of modulated electro-hyperthermia (mEHT) for the treatment of relapsed malignant glioma and astrocytoma versus best supportive care (BSC).

Protocol

•Device: Modulated Electro-Hyperthermia (mEHT)

EHY-2000 local machine is used for mEHT in the trial.

Modulated Electro-Hyperthermia (mEHT):

Pre-procedural medication administered to all patients before each mEHT to avoid brain edema was 250 ml of glycerol 18% and dexamethasone 12 mg to all patients before each mEHT session. The selected area was treated three times sessions per week for 8 weeks, and the treatment was prolonged if the tumor response was positive [complete response (CR); and partial response (PR); or stable disease (SD)]. The selected area was treated three times per week for 8 weeks. At three months the tumour response was assessed on CT or MRI scans and if the response was positive [complete response (CR); partial response (PR); or stable disease (SD)] then the 8 week course of treatment was repeated. The treatment time and the applied power was increased in each session according to the patient’s tolerance to heat. The first treatment was always performed applying 40 Watt for 20 minutes (48 kJ energy). Time was gradually raised from 20 to 60 minutes and also the power was increased according to a step-up power protocol from 40 up to 150 Watt (540 kJ) in two weeks.

- 20 minutes at PW=40 for two cycles

- 30 minutes at PW= 60 for two cycles

- 50 minutes at PW=80 for two cycles

•Drug: Best Supportive care

including dexamethasone, 18% glycerol infusion, mannitol, holistic therapy and psychosocial support. Nitrosoureas or cisplatin-based chemotherapies were allowed in the BSC protocol.

Eligibility Criteria

Inclusion Criteria:

· 18 years old,

· Eastern Cooperative Oncology Group (ECOG) performance status 0-3,

· normal values of standard hematological parameters.

•Normal function of bone marrow.

•Predicted survival time >1 month.

•Written informed consent.

Exclusion Criteria:

•Surgery within 3 weeks or not full recovery of postoperative suture.

•Emotional instability.

•Impossibility to place the patient into the mEHT machine.

•Electronic implanted devices anywhere.

•Missing or damaged heat-sense nerves or other field-sensitive issues in the treatment area.

•Very low white blood cell count (<1.5×10(9)/L), agranulocytosis (<0.5×10(9)/L) or severe anemia.

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) [ Time Frame: 8 weeks after start of treatment (4 weeks on completion of treatment) ]

•No Change (NC): less than 50% reduction of ascites, or no obvious reduction of ascites under ultrasound detection, or even increase of ascites, with obvious abdominal distention.

Secondary Outcome Measures

•Adverse Events Rate (AER) [ Time Frame: During 4 weeks of treatment course and 4 weeks after treatment]

Activation of the immune system, after failing immunotherapy, by mEHT induging antigen release

Background

Several locoregional procedures, such as trans-arterial catheter chemoembolization (mEHT), radiofrequency ablation (RFA) and cryoablation (CA), induce immunogenic cell death and peripheral immune response.

mEHT is particularly indicated for patients with advanced PERITONEAL CARCINOMATOSIS FROM COLON, OVARY AND GASTRIC CANCER and recently has been associated to immonutherapy. mEHT, indeed, can activate tumor immunogenicity by releasing tumor-associated antigen and by inducing the migration of cytotoxic T lymphocytes to small intrahepatic metastatic nodules.

Because of the emerging role of Immunotherapy for the treatment of PERITONEAL CARCINOMATOSIS FROM COLON, OVARY AND GASTRIC CANCER, this study aim to study the immune-profiling of PERITONEAL CARCINOMATOSIS FROM COLON, OVARY AND GASTRIC CANCER patients treated with mEHT associated to Immunotherapy.

The rationale, supporting the administration mEHT is that it will induce tumor-antigen release due to heat shoch response and apoptosis inducted by hyperthermia. This release of antigens may induce immunization of patients. In this way their immune system will be ready to recognize the tumor-antigen released as a consequence of the previous immunotherapy and to attack the tumor.

Hypothesis: The administration of mEHT can induce antigen release and hence activate the immune system, to potentiate the effects of the previous immunotherapy. This study aims to investigate the effect on immune system activation as a consequence of mEHT and consequent improvements of the tumor response after immunotherapy.

Condition or disease

Advanced Stage PERITONEAL CARCINOMATOSIS FROM COLON, OVARY AND GASTRIC CANCER

Objectives:

Primary objectives: to study the efficacy on immune system activation (immunological profile) of mEHT administered after immunotherapy for the treatment of peritoneal carcinomatosis from colon, ovary and gastric cancer)

Secondary objectives: Objective response rate (ORR), Progression free survival (PFS), Tumor response, Overall Survival (OS), adverse events

Trial Design: experimental, non randomized, one-arm, open label clinical trial

Treatment regimen

Device: Modulated Electro-Hyperthermia (mEHT)

EHY-2000 local machine is used for mEHT in the trial.

Modulated Electro-Hyperthermia (mEHT): 150 Watt x 60 min

| Expected number of patients : | 43 participants

Eligibility Criteria

Inclusion Criteria:

Signed informed consent form
Age >18 years
Diagnosis of advanced non resectable peritoneal carcinomatosis from colon, ovary and gastric cancer
Have measurable disease
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Patients must have adequate organ function defined by study-specified laboratory tests.
Evidence of post-menopausal status or negative pregnancy test
Willing and able to comply with study procedures

Exclusion Criteria:

Has participated in another investigational study during the last 6 months.
Major surgical procedure at the time of study enrollment or within 28 days prior to the first dose of IP.
Any contraindications for mEHT.
Has an active infection such as TB, HIV, hepatitis B or C.
History of active primary immunodeficiency.
Grade ≥2 neuropathy.
History or current use of immunosuppressive medications within 14 days prior to study medications.
Has an active known or suspected autoimmune disease.
Significant heart disease.
Woman who are pregnant or breastfeeding.
Known allergy or hypersensitivity to the study drug.

Outcome Measures

Primary endpoints:

to define the effects of mEHT (administered after immunotherapy) on immunological profile, defined as >30% rise of the parameters of interest: Total Lymphocytes( CD3+), CD3+/CD4+ (T-Helper Lymphocytes), CD3+/CD8+ (T-cytotoxic Lymphocytes),CD3+/CD56+ (NK Lymphocytes), CD19+ (B Lymphocytes), ratio CD4:CD8, Immunosum= T+B+NK. Immunoprofile will be assessed at baseline and every three months up to 1 year.

Secondary endpoints :

1. TAC or RMI will be performed every 3 moths until the end of Durvaluma treatment, and every 6 months during the 2 years of follow up.

Objective response rate (ORR) using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. [ Time Frame: 2 years ] Proportion of participants with reduction in tumor burden as defined by mRECIST criteria.
Progression free survival (PFS) [ Time Frame: 2 years ]Number of months until disease progression or death
Tumor response as determined by number of participants with partial (PR) or complete response (CR) as defined by mRECIST criteria [ Time Frame: 2 years ] PR is defined as >=30% reduction in size of target lesions, whereas CR is defined as disappearance of all target lesions
Overall Survival (OS) [ Time Frame: 2 years ] Number of months until death from any-cause

6. type and intensity of adverse events, Number of participants experiencing study drug-related toxicities [ Time Frame: 3 years ], Number of participants experiencing drug-related adverse events >= Grade 3 or higher as defined by CTCAE v5.0

Effects of Intraperitoneal hyperthermic Chemoinfusion (HIPEC) in Treatment of colon cancer: effects on the immune system, an observational prospective study

COLON-HIPEC-ADIUVANT

Aims

This trial studies the effects of HIPEC on the immune system activation in patients with colon cancer, comparing the efficacy of Standard colon resection versus Standard colon resection+ adiuvant HIPEC on activation of the immune system

Detailed Description

The peritoneum is the second most common site of recurrence in patients with colon cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult and adjuvant systemic treatment does not seem to affect peritoneal dissemination in contrast to haematogenous dissemination in the liver or lungs. Of all patients eventually presenting with clinically apparent PC, only a quarter have potentially curable disease. The curative option is cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC), but the effectiveness depends highly on the extent of disease and is associated with a considerable complication rate. HIPEC is the indicated treatment in clinical practice according to current international guidelines for patients at high risk of peritoneal carcinomatosis. Long term follow-up of patients treated with adjuvant HIPEC revealed no peritoneal recurrences. This result is in line with several published studies. Adjuvant HIPEC can reduce of 25 % the absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival.

This study wants to monitor the effects of HIPEC on immunological profile comparing the efficacy of Standard colon resection versus Standard colon resection+HIPEC

Protocol

Standard colon resection versus Standard colon resection+adiuvant HIPEC

•HIPEC according to clinical practice of Oncoteam group

Eligibility Criteria

Inclusion Criteria:

•Pathologically confirmed colon cancer locally advanced (T2N+, T3N+, T3N0)

•Karnofsky Performance Status (KPS) score ≥60%.

•Normal function of bone marrow.

•Predicted survival time >12 month.

•Written informed consent.

Exclusion Criteria:

•Surgery within 3 weeks or not full recovery of postoperative suture.

•Active bleeding or vascular occlusion in the mEHT treatment area.

•Emotional instability.

•Impossibility to place the patient into the mEHT machine.

•Metallic implants or replacements in the treatment area.

•Electronic implanted devices anywhere.

•Missing or damaged heat-sense nerves or other field-sensitive issues in the treatment area.

•Very low white blood cell count (<1.5×10(9)/L), agranulocytosis (<0.5×10(9)/L) or severe anemia.

Outcome Measures

Primary Outcome Measures

Effects of HIPEC on immunological profile, defined as >30% rise of the parameters of interest: Total Lymphocytes( CD3+), CD3+/CD4+ (T-Helper Lymphocytes), CD3+/CD8+ (T-cytotoxic Lymphocytes),CD3+/CD56+ (NK Lymphocytes), CD19+ (B Lymphocytes), ratio CD4:CD8, Immunosum= T+B+NK. Immunoprofile will be assessed at baseline and every three months up to 1 year

Objective Response Rate (ORR) [ Time Frame: 8 weeks after start of treatment (4 weeks on completion of treatment) ]

Secondary Outcome Measures

•Adverse Events Rate (AER) [ Time Frame: During 4 weeks of treatment course and 4 weeks after treatment]

Common Terminology Criteria for Adverse Events (CTCAE) (v4.03: June 14, 2010) U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES, National Institutes of Health, National Cancer Institute.