Ignite Creation Date:
2024-10-26 @ 3:43 PM
Last Modification Date:
2024-10-26 @ 3:43 PM
Study NCT ID:
NCT06647342
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-13
Brief Title:
The Effect of Reduced Bleomycin in Electrochemotherapy Treatment
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Randomised Controlled Clinical Trial Investigating the Effect of Reduced Bleomycin in Elechtrochemotherapy Treatment on Patients With Cutaneous Malignancies The BLESS Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
BLESS
Brief Summary:
The objective of this trial is to determine if reducing the chemotherapy dose in electrochemotherapy is equally effective as using the standard dose for treating various types of skin tumors
Electrochemotherapy involves administrating chemotherapy intravenously followed shortly by a brief electrical pulse to the tumor This pulses temporarily increases the tumor cells permeability allowing the chemotherapy to enter more effectively
Participants will undergo a single session of electrochemotherapy with either half the standard chemotherapy dose or the full standard dose The size of the cutaneous tumors will be measured before treatment and again three months after the treatment to compare their response in both groups To monitor the tumors as well as assess the adverse events and quality of life participants must attend follow-up visits at two weeks three months and twelve months Additional visits may be scheduled at one two four and six months if necessary as determined by the clinician or the patient Concentration of chemotherapy will be measured in blood samples and in samples from the treated tumor and normal skin
Electrochemotherapy involves administrating chemotherapy intravenously followed shortly by a brief electrical pulse to the tumor This pulses temporarily increases the tumor cells permeability allowing the chemotherapy to enter more effectively
Participants will undergo a single session of electrochemotherapy with either half the standard chemotherapy dose or the full standard dose The size of the cutaneous tumors will be measured before treatment and again three months after the treatment to compare their response in both groups To monitor the tumors as well as assess the adverse events and quality of life participants must attend follow-up visits at two weeks three months and twelve months Additional visits may be scheduled at one two four and six months if necessary as determined by the clinician or the patient Concentration of chemotherapy will be measured in blood samples and in samples from the treated tumor and normal skin
Detailed Description:
Introduction
Electroporation Electroporation is a method in which the cell is exposed to an external electric field resulting in increased permeability of the cell membrane 1 Electroporation is used to introduce drugs into cells without affecting intracellular organelles or cell viability By inducing this response drugs that are normally non-permeant eg hydrophilic chemotherapy such as bleomycin will enter the cell by diffusion thus enhancing the cytotoxic effect 2 3 The combination of electroporation and chemotherapy is known as electrochemotherapy ECT The application of the electric pulses causes vasoconstriction inducing drug entrapment due to reduced blood flow - this is termed the vascular lock 4 5 In addition electroporation also has a vascular-disrupting effect when combined with chemotherapy 4 ECT damages tumour vasculature leading to an additional cascade of tumour cell death due to lack of oxygen nutrients and waste product accumulation 5 These vascular changes are more prolonged in tumours than in normal tissue 6
Electrochemotherapy ECT is the combination of chemotherapy and electroporation in which electric pulses are administered to a tumour after intravenous or intratumoural injection of chemotherapy ECT has been shown to be effective in the treatment of cutaneous malignancies and is established as standard treatment for cutaneous primary and secondary skin tumours and ulcerating malignant wounds 7 8 ECT is often used as a one time treatment but can be repeated if necessary
Bleomycin is the drug of choice for ECT it has low toxicity to normal cells and the largest increase in efficacy after electroporation enhancing the cytotoxic effect with a factor 300 to 5000 9 ECT is performed in general or local anaesthesia depending on tumour location and size Patient preference and institutional practice is also taken into account 8
Bleomycin is an antineoplastic drug derived from Streptomyces verticillus and is used in the treatment of a variety of malignancies such as lymphoma and testicular cancer 11 Bleomycin generates single- and double-strand DNA breaks ie one molecule of bleomycin can cause 10-15 DNA strand breaks 12 Due to its hydrophilic nature the entry of bleomycin into cells is restricted and occurs via an endocytotic process 13 Bleomycin causes cell death in two ways depending on the doses used 1 if a lower amount of bleomycin is used thousands of bleomycin molecules the cell arrests in the G2-M phase enlarges and becomes polynucleated and dies slowly by necrosis 2 if a larger amount is used millions of bleomycin molecules pseudo-apoptosis kills the cell within a few minutes 12 14
Recently it has been shown that the disaccharide moiety of bleomycin facilitates uptake by cancer cells It is suggested that the upregulation of receptors associated with enhanced glycolysis in tumour cells could be the reason for bleomycin targeting tumour cells selectively 51
Bleomycin is degraded by an enzyme - bleomycin hydrolase - found in various normal tissues 11 A lower concentration of this enzyme is found in the skin and lungs which can lead to increased harms in these organs 15 16 The Danish Medicines Agency DMA states in its product summary that half of patients receiving bleomycin experience harms related to the skin erythema hyperpigmentation striae or soreness and one tenth experience pulmonary reactions with a minority 1 dying from pulmonary fibrosis 15 Some studies have observed that the risk of developing pulmonary toxicity from bleomycin is increased with age drug dose and concomitant oxygen therapy and thoracic radiation therapy 16
Since harms are associated with accumulative bleomycin dose it is desirable to investigate if the dose can be reduced to minimize risk of harms and maintain the same efficacy This may also enable some ineligible fragile patients to become eligible for ECT treatment eg lung cancer patients with a higher risk of developing pulmonary toxicity
Cutaneous malignancies A significant proportion of cancer patients develop cutaneous metastases 10 that often become exuding bleeding or odorous 17 18 Thus the metastases may influence patients quality of life 19 49 Cutaneous metastases negatively affect patients ie self-esteem body image and sexuality with feelings tied to frustration and loss of power 21 22 Most cancer patients receive chemotherapy or immunotherapy but some cancers do not respond to these standard treatments 23 ECT may be used for such cancers enhancing palliation and quality of life 3 24 The most frequently seen cutaneous metastases originate from breast cancer and occur in the chest region but may arise anywhere on the body and originate from most cancer types 20 The cutaneous malignancies may vary in size from a few millimetres to very large and may be focal or extensive
Clinical experience with electrochemotherapy In 1993 Belehradek and colleagues published the first clinical trial of ECT using bleomycin in 8 patients indicating that the treatment was well-tolerated by patients and with a clinical complete rumour response of 57 25 In 2003 Gothelf and colleagues reviewed the 11 clinical trials completed between 1993 and 2001 involving a total of 96 patients with 411 tumoursmetastases treated with different approaches 26 The overall response OR varied between 15 and 100 For the 11 ECT studies investigating bleomycin and ECT treatment on cutaneous malignancies the OR has been between 22 and 100 Three studies stand out with an OR of 22 28 and 45 respectively 27-29 The study by Domenge from 1996 was one of the first studies conducted on ECT and included only seven patients 27 In the studies by Matthiessen and Kreuter larger tumours gt3 cm were included It is well-known that the size of the tumour affects the response of the ECT treatment 29 When excluding these studies the OR varies from 58 to 100 The largest ECT bleomycin study by Clover and colleagues from 2020 included 987 patients with 2483 tumours 30 and showed that different tumours have different ORs for example basal cell carcinoma BCC and Kaposis sarcoma KS show the highest OR with 96 and 98 respectively while breast cancer metastases malignant melanoma MM and squamous cell carcinoma SCC have lower responses of 77 82 and 80 respectively This study also observed an effect of tumour size on the overall tumour response The highest response rates were observed in small tumours lt3 cm In small skin metastases lt2 cm no significant OR difference was observed between intravenous vs intratumoural administration of bleomycin however for larger skin metastases gt2cm the OR was significantly plt005 higher with intravenous administration 57 vs 48 30 Thus our trial will be stratified according to tumourmetastasis size
Clinical experience with reduced bleomycin In 1996 one of the first clinical ECT bleomycin studies with six patients used a bleomycin dose of 10000 IUm2 31 see Table 1 since medical and surgical oncologists believed that a dose of 22700 IUm2 - used in the first clinical trials - was too high This is the only study using this dose and from 1998 the standard dose of 15000 IUm2 was used in most studies
In 2016 a case report of a patient receiving ECT with bleomycin with a 50 reduced dose 7500 IUm2 due to renal dysfunction was published In this case a complete tumour response was observed 32
From 2013 to 2016 Rotunno identified via the International Network for Sharing Practices on Electrochemotherapy InspECT database 57 patients treated with ECT and reduced bleomycin 7500 10000 or 13500 IUm2 33 due to eg reduced renal function and high age Reduced bleomycin showed similar tumour response to a standard bleomycin dose 15000 IUm2 with an OR of 64 to 82 Thus the authors of the study suggested that reduced bleomycin doses could be as effective as the standard treatment - especially in patients with impaired renal function or patients eligible to multiple ECT cycles It was concluded that further research in order to find a personalized bleomycin dose is needed 33
In 2018 and 2021 two studies concluded that a reduced dose of bleomycin is a feasible treatment option for elderly patients with equal efficacy to standard dose treatment OR 87 to 100 and should be considered as a treatment in patients with comorbidities 34 35 In addition in a study by Groselj et al from 2018 it was suggested that the cosmetic outcome was improved with the use of a reduced dose of bleomycin compared to the standard dose due to shorter healing and less development of fibrous scarring tissue 36
Rationale for 50 bleomycin reduction in this study
Based on former literature 32-36 we find it realistic to reduce the bleomycin dose with 50 and still gain a sufficient overall tumour response after ECT treatment For time efficiency purposes in this study we have decided to investigate a 50 reduced dose of bleomycin only Randomisation to several bleomycin dose levels would subsequently result in the need of a significant increase in the number of included patients andor referring hospital departments which would be time consuming and difficult to complete within a manageable time frame
Methods Trial design The study design as a non-inferiority study and is a parallel two-armed double-blinded randomized clinical trial where the patients are stratified due to the size of their biggest cutaneous tumour 3 cm or gt 3 cm and afterwards randomized 11 to receive a standard dose bleomycin or a 50 reduced dose bleomycin
Blinding is performed by the pharmacy mixing the allotted dose regimen after randomization both patients and treating staff will be blinded to the bleomycin dose Unblinding will be performed according to procedure if need be Unblinding of all results will take place after last patients evaluation of primary endpoint
The study will be conducted at two centers in Denmark At the department of Clinical Oncology and Palliative Care Zealand University Hospital Roskilde and at the Department of Oncology Copenhagen University Hospital Herlev Gentofte Hospital The three year study period is expected to start in October 2024
Study population Patients will be referred from oncologic departments and must be advised about treatment alternatives It must be evaluated whether the patient will benefit from the treatment given the localisation and size of the tumourtumours the patients general condition and expected survival The purpose possible risks and benefits should be discussed in collaboration with the patient
Indications for participating in this trial includes
Biopsy verified cutaneous malignancies of any histology which are symptomatic due to bleeding ulceration oozing odour or pain
Primary skin cancers including recurrent tumours where other treatment modalities have failed are not possible or not appropriate
Patients who are receiving systematic anti-neoplastic therapy but where cutaneous metastases are progressing or not responding despite satisfactory response to systemic therapy in internal organs
Patient preference for electrochemotherapy after other treatment possibilities have been thoroughly explained to the patient For eligibility criteria please refer to the section about eligibility criteria
Pre-treatment examination and pain management
The pre-treatment examination will be performed up to one month prior to the procedure and will include diagnosis of primary tumour TNM tumour node and metastasis classification and previous anti-neoplastic treatments Under previous treatments it must be noted which nodules have been treated with which treatment Radiotherapy fields or other local treatments must be listed if nodules were subjected to this Additionally assessment of medical history previous problems with anaesthesia any other relevant medical history combination with other treatments and presence of symptoms will be noted A physical examination with clinical assessment of the tumour location and availability of electroporation will be made All the cutaneous tumours of the patient will be treated but a maximum of seven tumours per patient will be registered and followed over time and only one tumour will be selected for tissue biopsies
Moreover assessment of performance status will be performed and pre-existing pain problems will be examined in order to create a pain management plan
Treatment day Anaesthesia As this is a study including treatment with intravenous bleomycin participants will in most cases receive general anaesthesia administered according to institutional guidelines or standard operating procedures 52 In cases where local anaesthetics are preferable this can also be utilized and administered according to institutional guidelines
Bleomycin dose Bleomycin is the approved chemotherapeutic drug for use in ECT and will be used according to the marketing authorization in this trial
In order to calculate the body surface area BSA the patients height will be noted and their weight measured Patients will receive either a standard dose of bleomycin 15000 IUm2 BSA or a dose reduced with 50 7500 IUm2 BSA intravenously Bleomycin is infused over a short time 2-5 min and 8 min after completion of the infusion the drug has diffused into tumour tissues and hereafter the electric pulses can be applied
Applied electric pulses The electric pulses will be administered 8 minutes after bleomycin infusion It is important that the entire tumour volume with surrounding tissue is treated with electroporation so a margin of 3 mm around the tumour is included in the treatment
For electroporation we use the Cliniporator model EPS02 IGEA Carpi Italy square wave pulse generator which delivers a series of eight consecutive pulses of 01 msec each with an amplitude of 1 kVcm and a frequency of 1 Hz The electrodes will be chosen according to the standard operating procedures 8 depending on size and anatomical location of the tumour
All tumours will be treated but a maximum of seven tumours per patient will be followed and only one tumour will be selected for tissue biopsies
Biological samples Two biopsies from normal skin surrounding the tumour will be collected one before bleomycin infusion and one 8 minutes after bleomycin infusion Five biopsies will be collected from each patient from one of the tumours at the time points before bleomycin infusion 2 4 6 and 8 minutes after bleomycin infusion An additional tumour biopsy will be collected before bleomycin infusion for histologic analysis this biopsy will optional to the patient be repeated after one year The biopsies will include 3 mm tissue per biopsy and a maximum of 075 ml
Six blood samples will be collected at predetermined time points at treatment day before bleomycin infusion 5 10 20 30 and 40 min after bleomycin administration
The blood and biopsies except those made for histological analysis will be analysed at the Department of Science and Environment at Roskilde University according to the amount of bleomycin Here the HPLC machine will be used to detect the All blood samples will be stored in a collective bio bank situated at Region Zealand Biobank approved by the Danish Data Protection Agency
Follow up Mandatory follow-ups occur at 2 weeks 3 months and 12 months Optional follow-up consultations will be possible at 30 60 120 and 180 days after ECT treatment The necessity of these optional consultations will be decided by the physician and patient
Each target tumour size will be assessed with a ruler and documented with photographys before treatment and at all the follow up consultations At 3 months and 12 months evaluation of wound healing and scar formation will be accessed by three independent observers 1 plastic surgeon 1 oncologist and 1 research associate using the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale Moreover quality of life EORTC-questionnaires will be performed At all follow-up consultations pain from the tumours and adverse events will be measured
For primary and secondary endpoints please refer to the relevant sections
Methods employed for evaluation of quality of life Patients will be asked to answer the European Organisation for Research and Treatment of Cancer EORTC QLQ-C30 questionnaire at month 0 3 and 12 This questionnaire is developed to assess the quality of life of cancer patients
Additionally 16 patients will participate in a qualitative interview at baseline and at month 3 if they give separate consent This is in order to learn about patient experiences with treatment and to assess ECT treatment impact on quality of life In this study qualitative interviews may uncover concerns and priorities that distinguish cancer patients with cutaneous malignancies from other patients and thereby help to sufficiently capture the patients experience 38 To collect patient experiences semi-structured interview is chosen as it gives the researcher the freedom to probe the interviewee to elaborate or to follow a new line of inquiry introduced by what the interviewee is saying
Sample size
This is a non-inferiority study where the primary endpoint is to compare overall response at tumour level three months after ECT treatment with two different doses of bleomycin The appropriate sample size is calculated to determine the minimum number of tumours that need to be treated in this study in order to have a sufficient statistical power showing that halving the dose of bleomycin is non-inferior to the standard dose
To calculate the sample size we utilized the formula for non-inferiority study with continuous data 37 The standard deviation was derived from 55 studies from 1996 - 2021 exploring electrochometherapy with intravenous bleomycin in different tumour histologies 38 We assumed an acceptable response rate difference on 10 The significance level where set at 005 with 80 power Based on the findings on five previous studies where there was observed a drop-out rate at 16 30 39-42 we conservatively estimated a drop-out rate at 20 This led to the conclusion that 110 tumours needed to be treated in this study Anticipating an average of approximately 2 tumours per patient to be evaluated as observed in previous literature 30 we plan to enroll 55 patients
Recruitment Patients will be recruited from four departments the Department of Clinical Oncology and Palliative Care and the Department of Plastic and Breast Surgery at Zealand University Hospital Roskilde and Department of Oncology and Department of Plastic Surgery at Herlev Hospital respectively Patients eligible for treatment might be referred from other departments throughout Denmark
End of Trial The trial will conclude when 55 patients have been enrolled have received ECT and the last patient has completed their final scheduled follow-up 12 months after ECT
Electroporation Electroporation is a method in which the cell is exposed to an external electric field resulting in increased permeability of the cell membrane 1 Electroporation is used to introduce drugs into cells without affecting intracellular organelles or cell viability By inducing this response drugs that are normally non-permeant eg hydrophilic chemotherapy such as bleomycin will enter the cell by diffusion thus enhancing the cytotoxic effect 2 3 The combination of electroporation and chemotherapy is known as electrochemotherapy ECT The application of the electric pulses causes vasoconstriction inducing drug entrapment due to reduced blood flow - this is termed the vascular lock 4 5 In addition electroporation also has a vascular-disrupting effect when combined with chemotherapy 4 ECT damages tumour vasculature leading to an additional cascade of tumour cell death due to lack of oxygen nutrients and waste product accumulation 5 These vascular changes are more prolonged in tumours than in normal tissue 6
Electrochemotherapy ECT is the combination of chemotherapy and electroporation in which electric pulses are administered to a tumour after intravenous or intratumoural injection of chemotherapy ECT has been shown to be effective in the treatment of cutaneous malignancies and is established as standard treatment for cutaneous primary and secondary skin tumours and ulcerating malignant wounds 7 8 ECT is often used as a one time treatment but can be repeated if necessary
Bleomycin is the drug of choice for ECT it has low toxicity to normal cells and the largest increase in efficacy after electroporation enhancing the cytotoxic effect with a factor 300 to 5000 9 ECT is performed in general or local anaesthesia depending on tumour location and size Patient preference and institutional practice is also taken into account 8
Bleomycin is an antineoplastic drug derived from Streptomyces verticillus and is used in the treatment of a variety of malignancies such as lymphoma and testicular cancer 11 Bleomycin generates single- and double-strand DNA breaks ie one molecule of bleomycin can cause 10-15 DNA strand breaks 12 Due to its hydrophilic nature the entry of bleomycin into cells is restricted and occurs via an endocytotic process 13 Bleomycin causes cell death in two ways depending on the doses used 1 if a lower amount of bleomycin is used thousands of bleomycin molecules the cell arrests in the G2-M phase enlarges and becomes polynucleated and dies slowly by necrosis 2 if a larger amount is used millions of bleomycin molecules pseudo-apoptosis kills the cell within a few minutes 12 14
Recently it has been shown that the disaccharide moiety of bleomycin facilitates uptake by cancer cells It is suggested that the upregulation of receptors associated with enhanced glycolysis in tumour cells could be the reason for bleomycin targeting tumour cells selectively 51
Bleomycin is degraded by an enzyme - bleomycin hydrolase - found in various normal tissues 11 A lower concentration of this enzyme is found in the skin and lungs which can lead to increased harms in these organs 15 16 The Danish Medicines Agency DMA states in its product summary that half of patients receiving bleomycin experience harms related to the skin erythema hyperpigmentation striae or soreness and one tenth experience pulmonary reactions with a minority 1 dying from pulmonary fibrosis 15 Some studies have observed that the risk of developing pulmonary toxicity from bleomycin is increased with age drug dose and concomitant oxygen therapy and thoracic radiation therapy 16
Since harms are associated with accumulative bleomycin dose it is desirable to investigate if the dose can be reduced to minimize risk of harms and maintain the same efficacy This may also enable some ineligible fragile patients to become eligible for ECT treatment eg lung cancer patients with a higher risk of developing pulmonary toxicity
Cutaneous malignancies A significant proportion of cancer patients develop cutaneous metastases 10 that often become exuding bleeding or odorous 17 18 Thus the metastases may influence patients quality of life 19 49 Cutaneous metastases negatively affect patients ie self-esteem body image and sexuality with feelings tied to frustration and loss of power 21 22 Most cancer patients receive chemotherapy or immunotherapy but some cancers do not respond to these standard treatments 23 ECT may be used for such cancers enhancing palliation and quality of life 3 24 The most frequently seen cutaneous metastases originate from breast cancer and occur in the chest region but may arise anywhere on the body and originate from most cancer types 20 The cutaneous malignancies may vary in size from a few millimetres to very large and may be focal or extensive
Clinical experience with electrochemotherapy In 1993 Belehradek and colleagues published the first clinical trial of ECT using bleomycin in 8 patients indicating that the treatment was well-tolerated by patients and with a clinical complete rumour response of 57 25 In 2003 Gothelf and colleagues reviewed the 11 clinical trials completed between 1993 and 2001 involving a total of 96 patients with 411 tumoursmetastases treated with different approaches 26 The overall response OR varied between 15 and 100 For the 11 ECT studies investigating bleomycin and ECT treatment on cutaneous malignancies the OR has been between 22 and 100 Three studies stand out with an OR of 22 28 and 45 respectively 27-29 The study by Domenge from 1996 was one of the first studies conducted on ECT and included only seven patients 27 In the studies by Matthiessen and Kreuter larger tumours gt3 cm were included It is well-known that the size of the tumour affects the response of the ECT treatment 29 When excluding these studies the OR varies from 58 to 100 The largest ECT bleomycin study by Clover and colleagues from 2020 included 987 patients with 2483 tumours 30 and showed that different tumours have different ORs for example basal cell carcinoma BCC and Kaposis sarcoma KS show the highest OR with 96 and 98 respectively while breast cancer metastases malignant melanoma MM and squamous cell carcinoma SCC have lower responses of 77 82 and 80 respectively This study also observed an effect of tumour size on the overall tumour response The highest response rates were observed in small tumours lt3 cm In small skin metastases lt2 cm no significant OR difference was observed between intravenous vs intratumoural administration of bleomycin however for larger skin metastases gt2cm the OR was significantly plt005 higher with intravenous administration 57 vs 48 30 Thus our trial will be stratified according to tumourmetastasis size
Clinical experience with reduced bleomycin In 1996 one of the first clinical ECT bleomycin studies with six patients used a bleomycin dose of 10000 IUm2 31 see Table 1 since medical and surgical oncologists believed that a dose of 22700 IUm2 - used in the first clinical trials - was too high This is the only study using this dose and from 1998 the standard dose of 15000 IUm2 was used in most studies
In 2016 a case report of a patient receiving ECT with bleomycin with a 50 reduced dose 7500 IUm2 due to renal dysfunction was published In this case a complete tumour response was observed 32
From 2013 to 2016 Rotunno identified via the International Network for Sharing Practices on Electrochemotherapy InspECT database 57 patients treated with ECT and reduced bleomycin 7500 10000 or 13500 IUm2 33 due to eg reduced renal function and high age Reduced bleomycin showed similar tumour response to a standard bleomycin dose 15000 IUm2 with an OR of 64 to 82 Thus the authors of the study suggested that reduced bleomycin doses could be as effective as the standard treatment - especially in patients with impaired renal function or patients eligible to multiple ECT cycles It was concluded that further research in order to find a personalized bleomycin dose is needed 33
In 2018 and 2021 two studies concluded that a reduced dose of bleomycin is a feasible treatment option for elderly patients with equal efficacy to standard dose treatment OR 87 to 100 and should be considered as a treatment in patients with comorbidities 34 35 In addition in a study by Groselj et al from 2018 it was suggested that the cosmetic outcome was improved with the use of a reduced dose of bleomycin compared to the standard dose due to shorter healing and less development of fibrous scarring tissue 36
Rationale for 50 bleomycin reduction in this study
Based on former literature 32-36 we find it realistic to reduce the bleomycin dose with 50 and still gain a sufficient overall tumour response after ECT treatment For time efficiency purposes in this study we have decided to investigate a 50 reduced dose of bleomycin only Randomisation to several bleomycin dose levels would subsequently result in the need of a significant increase in the number of included patients andor referring hospital departments which would be time consuming and difficult to complete within a manageable time frame
Methods Trial design The study design as a non-inferiority study and is a parallel two-armed double-blinded randomized clinical trial where the patients are stratified due to the size of their biggest cutaneous tumour 3 cm or gt 3 cm and afterwards randomized 11 to receive a standard dose bleomycin or a 50 reduced dose bleomycin
Blinding is performed by the pharmacy mixing the allotted dose regimen after randomization both patients and treating staff will be blinded to the bleomycin dose Unblinding will be performed according to procedure if need be Unblinding of all results will take place after last patients evaluation of primary endpoint
The study will be conducted at two centers in Denmark At the department of Clinical Oncology and Palliative Care Zealand University Hospital Roskilde and at the Department of Oncology Copenhagen University Hospital Herlev Gentofte Hospital The three year study period is expected to start in October 2024
Study population Patients will be referred from oncologic departments and must be advised about treatment alternatives It must be evaluated whether the patient will benefit from the treatment given the localisation and size of the tumourtumours the patients general condition and expected survival The purpose possible risks and benefits should be discussed in collaboration with the patient
Indications for participating in this trial includes
Biopsy verified cutaneous malignancies of any histology which are symptomatic due to bleeding ulceration oozing odour or pain
Primary skin cancers including recurrent tumours where other treatment modalities have failed are not possible or not appropriate
Patients who are receiving systematic anti-neoplastic therapy but where cutaneous metastases are progressing or not responding despite satisfactory response to systemic therapy in internal organs
Patient preference for electrochemotherapy after other treatment possibilities have been thoroughly explained to the patient For eligibility criteria please refer to the section about eligibility criteria
Pre-treatment examination and pain management
The pre-treatment examination will be performed up to one month prior to the procedure and will include diagnosis of primary tumour TNM tumour node and metastasis classification and previous anti-neoplastic treatments Under previous treatments it must be noted which nodules have been treated with which treatment Radiotherapy fields or other local treatments must be listed if nodules were subjected to this Additionally assessment of medical history previous problems with anaesthesia any other relevant medical history combination with other treatments and presence of symptoms will be noted A physical examination with clinical assessment of the tumour location and availability of electroporation will be made All the cutaneous tumours of the patient will be treated but a maximum of seven tumours per patient will be registered and followed over time and only one tumour will be selected for tissue biopsies
Moreover assessment of performance status will be performed and pre-existing pain problems will be examined in order to create a pain management plan
Treatment day Anaesthesia As this is a study including treatment with intravenous bleomycin participants will in most cases receive general anaesthesia administered according to institutional guidelines or standard operating procedures 52 In cases where local anaesthetics are preferable this can also be utilized and administered according to institutional guidelines
Bleomycin dose Bleomycin is the approved chemotherapeutic drug for use in ECT and will be used according to the marketing authorization in this trial
In order to calculate the body surface area BSA the patients height will be noted and their weight measured Patients will receive either a standard dose of bleomycin 15000 IUm2 BSA or a dose reduced with 50 7500 IUm2 BSA intravenously Bleomycin is infused over a short time 2-5 min and 8 min after completion of the infusion the drug has diffused into tumour tissues and hereafter the electric pulses can be applied
Applied electric pulses The electric pulses will be administered 8 minutes after bleomycin infusion It is important that the entire tumour volume with surrounding tissue is treated with electroporation so a margin of 3 mm around the tumour is included in the treatment
For electroporation we use the Cliniporator model EPS02 IGEA Carpi Italy square wave pulse generator which delivers a series of eight consecutive pulses of 01 msec each with an amplitude of 1 kVcm and a frequency of 1 Hz The electrodes will be chosen according to the standard operating procedures 8 depending on size and anatomical location of the tumour
All tumours will be treated but a maximum of seven tumours per patient will be followed and only one tumour will be selected for tissue biopsies
Biological samples Two biopsies from normal skin surrounding the tumour will be collected one before bleomycin infusion and one 8 minutes after bleomycin infusion Five biopsies will be collected from each patient from one of the tumours at the time points before bleomycin infusion 2 4 6 and 8 minutes after bleomycin infusion An additional tumour biopsy will be collected before bleomycin infusion for histologic analysis this biopsy will optional to the patient be repeated after one year The biopsies will include 3 mm tissue per biopsy and a maximum of 075 ml
Six blood samples will be collected at predetermined time points at treatment day before bleomycin infusion 5 10 20 30 and 40 min after bleomycin administration
The blood and biopsies except those made for histological analysis will be analysed at the Department of Science and Environment at Roskilde University according to the amount of bleomycin Here the HPLC machine will be used to detect the All blood samples will be stored in a collective bio bank situated at Region Zealand Biobank approved by the Danish Data Protection Agency
Follow up Mandatory follow-ups occur at 2 weeks 3 months and 12 months Optional follow-up consultations will be possible at 30 60 120 and 180 days after ECT treatment The necessity of these optional consultations will be decided by the physician and patient
Each target tumour size will be assessed with a ruler and documented with photographys before treatment and at all the follow up consultations At 3 months and 12 months evaluation of wound healing and scar formation will be accessed by three independent observers 1 plastic surgeon 1 oncologist and 1 research associate using the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale Moreover quality of life EORTC-questionnaires will be performed At all follow-up consultations pain from the tumours and adverse events will be measured
For primary and secondary endpoints please refer to the relevant sections
Methods employed for evaluation of quality of life Patients will be asked to answer the European Organisation for Research and Treatment of Cancer EORTC QLQ-C30 questionnaire at month 0 3 and 12 This questionnaire is developed to assess the quality of life of cancer patients
Additionally 16 patients will participate in a qualitative interview at baseline and at month 3 if they give separate consent This is in order to learn about patient experiences with treatment and to assess ECT treatment impact on quality of life In this study qualitative interviews may uncover concerns and priorities that distinguish cancer patients with cutaneous malignancies from other patients and thereby help to sufficiently capture the patients experience 38 To collect patient experiences semi-structured interview is chosen as it gives the researcher the freedom to probe the interviewee to elaborate or to follow a new line of inquiry introduced by what the interviewee is saying
Sample size
This is a non-inferiority study where the primary endpoint is to compare overall response at tumour level three months after ECT treatment with two different doses of bleomycin The appropriate sample size is calculated to determine the minimum number of tumours that need to be treated in this study in order to have a sufficient statistical power showing that halving the dose of bleomycin is non-inferior to the standard dose
To calculate the sample size we utilized the formula for non-inferiority study with continuous data 37 The standard deviation was derived from 55 studies from 1996 - 2021 exploring electrochometherapy with intravenous bleomycin in different tumour histologies 38 We assumed an acceptable response rate difference on 10 The significance level where set at 005 with 80 power Based on the findings on five previous studies where there was observed a drop-out rate at 16 30 39-42 we conservatively estimated a drop-out rate at 20 This led to the conclusion that 110 tumours needed to be treated in this study Anticipating an average of approximately 2 tumours per patient to be evaluated as observed in previous literature 30 we plan to enroll 55 patients
Recruitment Patients will be recruited from four departments the Department of Clinical Oncology and Palliative Care and the Department of Plastic and Breast Surgery at Zealand University Hospital Roskilde and Department of Oncology and Department of Plastic Surgery at Herlev Hospital respectively Patients eligible for treatment might be referred from other departments throughout Denmark
End of Trial The trial will conclude when 55 patients have been enrolled have received ECT and the last patient has completed their final scheduled follow-up 12 months after ECT
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None