Modulated Electro-Hyperthermia Plus Chemo-radiation for Locally Advanced Cervical Cancer Patients in South Africa

Study Overview
=================
Brief Summary
-----------------
This is a phase III randomised clinical trial. The aim is to investigate the clinical effects of the addition of modulated electro-hyperthermia (mEHT) to standard treatment protocols (chemoradiotherapy, CRT) for Human Immunodeficiency Virus (HIV) positive and negative locally advanced cervical cancer patients (LACC). SAMPLE: The investigators aim to enrol 236 HIV negative and HIV positive women with LACC, FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) Stages IIB (distil) to stage III. Participants will be randomly assigned to a control group (N=118) and a study group (N=118). METHODOLOGY: Randomisation is based on age, stage and HIV. Participants from both groups will receive the standard treatment for cervical cancer at the hospital at the Charlotte Maxeke Johannesburg Academic Hospital in South Africa: Up to three doses of 80mg/m2 cisplatin, administered three weeks apart; 50Gy external beam radiation (EBR) in fractions of 2Gy; Three doses of 8Gy High Dose Rate (HDR) brachytherapy. The study group will have two 55 minute mEHT treatments per week, at 130W, directly before the EBR using the EHY 2000 Device. OUTCOMES: 1) Determine the local disease control after treatment at 6 months using a Positron Emission Tomography (PET) and computerised tomography (CT) scans. 2) Determine the progression-free survival (PFS) at 6, 12, 18 and 24 months after the last treatment date. PFS will be assessed in all registered participants, regardless of completion (Intent to Treat-ITT) as well as only in the subset of participants who complete the prescribed CRT. 3) Overall survival at two years will be assessed. 4) To evaluate the adverse events associated with mEHT. 5) The effect of mEHT on chemotherapy and radiotherapy tolerability and toxicity will be evaluated. 6) The quality of life of enrolled participants will be assessed before, at 6 weeks, and at 3, 6, 9, 12, 18 and 24 months after completion of therapy using the EORTC (European Organisation for Research and Treatment of Cancer) and EuroQoL forms. 7) To evaluate the economic viability of the addition of mEHT to standard treatment protocols for LACC. 8) The effect, if any, of mEHT treatments on the HIV disease status of HIV positive patients will be assessed by the presence of Autoimmune Deficiency Syndrome (AIDS) defining illnesses before and after treatment. 9) The cancer recurrence patterns will be described and compared in all the participants.

Official Title
-----------------
A Phase III Randomised Trial Investigating the Benefits of the Addition of Modulated Electro-hyperthermia to Chemo-radiation for Cervical Cancer in HIV Positive and Negative Women in South Africa

Conditions
-----------------
Cervical Cancer

Intervention / Treatment
-----------------
* Device: Modulated electro-hyperthermia
* Radiation: External beam radiation
* Drug: Cisplatin
* Radiation: Brachytherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants (who have been adequately clinically staged by standard clinical guidelines) with biopsy proven primary, untreated, histologically confirmed invasive squamous and aden-squamous cell carcinoma of the uterine cervix, FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) stages advanced IIB (invasion of the distal half of the parametrium), IIIA and IIIB. HIV positive participants will be accepted. The following laboratory tests will be done prior to enrolment in the study and the values must be in the following ranges: Haemoglobin >10 g/dL; Platelet count >150/mm3; Absolute neutrophil count (ANC) >3000/mm3 Creatinine clearance>60 mL/min Liver function tests Females between the ages of 18 and 70 years. Ability to understand and the willingness to sign a written informed consent document. Eastern Cooperative Oncology Group (ECOG) score of not more than 2. Participants of childbearing potential must have a negative urine or serum pregnancy test prior to enrolment and use an effective form of contraception (e.g. barrier contraception, highly effective hormonal contraception). At the investigators' discretion, participants must be suitable for treatment with radical intent using concurrent chemotherapy and pelvic radiation. Subjects who undergo emergency RT in the form of brachytherapy for haemostasis, prior to enrolment will be allowed to be screened and enrolled provided they meet all other eligibility criteria. Life expectancy of greater than 12 months. Participants must have a body mass index (BMI) that is within normal ranges. - Exclusion Criteria: Participants who have undergone hysterectomy. Exclude para-aortic lymph involvement on planning CT (without contrast) Patients with life-threatening AIDS defining illnesses (other than cervical carcinoma) will be excluded, as will patients with a CD4 count < 200/µL and not on ARVs. Patients with acute active (such as tuberculosis or malaria), serious, uncontrolled infections will be excluded. Participants will be excluded if there is evidence of resistance to antiretroviral therapy (i.e. HIV viral load > 400 copies/mL despite combination antiretroviral therapy for at least 4 months). Prior invasive malignancy other than cervical cancer, diagnosed within the past 24 months, excluding in situ anal dysplasia or carcinoma in situ, non-melanoma skin carcinoma, or Kaposi's sarcoma that has not required systemic chemotherapy within the past 24 months. Pregnant or breast-feeding women. A medical or psychiatric illness that prevents the participant from being able to sign an informed consent or would affect the participant's ability to comply with the protocol stipulations. Participants with circumstances that will not permit completion of the study or required follow-ups. For instance if travel to and from treatment site is an issue. Participants with carcinoma of the cervical stump. Participants with a history of cardiovascular disease manifested as History of myocardial infarction Unstable angina Currently taking medication for treatment of angina History of coronary artery bypass surgery Participants with contraindications to modulated electro-hyperthermia treatment: Pace makers and other implanted devices which rely on current and charges. Large metal implants, such as hip replacements. Inability to feel temperature in the region. Inability to express or vocalise discomfort or heat at the treatment site.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study<br>50 Gy external beam radiation administered in fractions of 2 Gy 3 Doses of 8 Gy High Dose Rate brachytherapy up to 3 doses of 80mg/m2 of Cisplatin 10 modulated electro-hyperthermia treatments (55 minutes at a maximum of 150W) | Device: Modulated electro-hyperthermia<br>* Modulated electro-hyperthermia device used is the EHY 2000 by Oncotherm GmbH<br>* Other names: Nanothermia;Radiation: External beam radiation<br> <br> * Other names: Radiotherapy;Drug: Cisplatin<br> <br> * Other names: Chemotherapy;Radiation: Brachytherapy<br>* High Dose Rate<br>* Other names: Radiation therapy;|
| Active Comparator: Control<br>50 Gy external beam radiation administered in fractions of 2 Gy 3 Doses of 8 Gy High Dose Rate brachytherapy up to 3 doses of 80mg/m2 of Cisplatin | Radiation: External beam radiation<br> <br> * Other names: Radiotherapy;Drug: Cisplatin<br> <br> * Other names: Chemotherapy;Radiation: Brachytherapy<br>* High Dose Rate<br>* Other names: Radiation therapy;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Local Disease Control | Assessed by PET/CT using the RESIST/PERSIST criteria: complete response, complete metabolic response, partial response, stable disease, progressive disease. | 6 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | To determine the progression-free survival (PFS) at 6, 12, 18 and 24 months after the last treatment date. Determine PFS in all registered participants, regardless of completion (Intent To Treat-ITT) Determine PFS in the subset of participants who complete the prescribed chemo-radiotherapy | 24 months post treatment | 
| 2 Year Survival | Determine the overall survival at two years and the cause of death (i.e. cancer-related, HIV-related, treatment related or other). | 24 months post treatment | 
| Incidence of Adverse Events Attributed to mEHT as assessed by CTCAE version 4.0 | To evaluate the adverse events that can be directly attributed to mEHT treatments. | 6 months post treatment | 
| Incidence of Treatment Related Adverse Events Attributed to Cisplatin as assessed by CTCAE version 4.0 | The incidence of treatment-emergent adverse events which can be attributed to Cisplatin in each arm will be compared in order to identify any potential effect of mEHT on the frequency and severity of adverse events attributed to Cisplatin. | Up to 3 months post treatment completion | 
| Number of participants with Early Treatment Related Adverse Events as assessed by CTCAE version 4.0 | The incidence of early toxicity symptoms (graded using the CTCAE version 4 criteria) associated with radiotherapy in each arm of the study will be compared to identify any potential effect of the mEHT on the incidence and severity of early toxicity. | Up to 6 months post treatment completion | 
| Number of participants with Late Treatment Related Adverse Events as assessed by CTCAE version 4.0 | The incidence of late toxicity symptoms (graded using the CTCAE version 4 criteria) associated with radiotherapy in each arm of the study will be compared to identify any potential effect of the mEHT on the incidence of late toxicity in the sample group. | Up to 24 months post treatment completion | 
| Visual Analogue Scale On the EuroQoL EQ-5D-5L form | To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Visual Analogue Scale on the EuroQoL EQ-5D-5L form | Up to 24 months post treatment completion | 
| Mobility On the EuroQoL EQ-5D-5L form | To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Mobility on the EuroQoL EQ-5D-5L form | Up to 24 months post treatment completion | 
| Self-Care On the EuroQoL EQ-5D-5L form | To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Self-Care on the EuroQoL EQ-5D-5L form | Up to 24 months post treatment completion | 
| Usual Activities On the EuroQoL EQ-5D-5L form | To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Usual Activities on the EuroQoL EQ-5D-5L form | Up to 24 months post treatment completion | 
| Pain/Discomfort On the EuroQoL EQ-5D-5L form | To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Pain/Discomfort on the EuroQoL EQ-5D-5L form | Up to 24 months post treatment completion | 
| Anxiety/Depression On the EuroQoL EQ-5D-5L form | To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Anxiety/Depression on the EuroQoL EQ-5D-5L form | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Global Health Status | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Global Health Status | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Physical Functioning | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Physical Functioning | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Role Functioning | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Role Functioning | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Emotional Functioning | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Emotional Functioning | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Cognitive Functioning | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Cognitive Functioning | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Social Functioning | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Social Functioning | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Fatigue | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Fatigue | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Nausea and Vomiting | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Nausea and Vomiting | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Pain | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Pain | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Dyspnoea | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Dyspnoea | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Insomnia | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Insomnia | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Appetite Loss | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Appetite Loss | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Constipation | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Constipation | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Diarrhoea | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Diarrhoea | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 30 for Financial Difficulties | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Financial Difficulties | Up to 24 months post treatment completion | 
| Score on the EORTC-QLQ 24 for Symptom Experiences | To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Symptom Experiences | Up to 24 months post treatment completion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cervix, Hyperthermia, HIV