investigational plan "multi-center open-labeled nonrandomized
9.3.2 causality

The relationship between the use of the medical device and the occurrence of each AE shall be assessed and categorized. During causality assessment activity, clinical judgement shall be used and the relevant documents, such as the IB and the Clinical Investigational Plan (CIP)
shall be consulted. The presence of confounding factors, such as concomitant medication/treatment, the natural history of the underlying disease, other concurrent illness or risk factors shall also be considered. The investigator will assess the reasonable possibility that the study medical device either caused or contributed to the AE.  
The Sponsor and the investigators will use the following definitions to assess the relationship of the AE to the investigational medical device:
Not related: relationship to the device or procedures can be excluded when:  
o the event is not a known side effect of the product category the device belongs to or of similar devices; o the event has no temporal relationship with the use of the investigational device or the procedures; o the discontinuation of the medical device application does not impact on the event:
o the event involves a body-site or an organ not expected to be affected by the device.  
o the serious event can be attributed to another cause (e.g. an underlying or concurrent illness/ clinical condition, an effect of another device, drug, treatment or other risk factors);
o harms to the subject are not clearly due to use error; o In order to establish the non-relatedness, not all the criteria listed above might be met at the same time, depending on the type of device/procedures and the event.  
Unlikely: the relationship with the use of the device seems not relevant and/or the event can be reasonably explained by another cause, but additional information may be obtained.  
Possible: the relationship with the use of the investigational device is weak but cannot be ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical condition or/and an effect of another device, drug or treatment). Cases were relatedness cannot be assessed or no information has been obtained should also be classified as possible.  
Probable: the relationship with the use of the investigational device seems relevant and/or the event cannot reasonably be explained by another cause, but additional information may be obtained.  
Causal relationship: the adverse event is associated with the investigational device or with procedures beyond reasonable doubt when:
o the event is a known side effect of the product category the device belongs to or of similar devices and procedures; o the event has a temporal relationship with investigational device use/application or procedures; o the event involves a body-site or organ that the investigational device is applied to the investigational device has an effect on; o the event follows a known response pattern to the medical device (if the response pattern is previously known);
o other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an effect of another device, drug or treatment) have been adequately ruled out; o harm to the subject is due to error in use;
o To establish the relatedness, not all the criteria listed above might be met at the same time, depending on the type of device and the serious event.  
The Sponsor and the investigators will distinguish between the AEs related to the investigational device and those related to the procedures (any procedure specific to the clinical investigation).  
An AE can be related both to procedures and the investigational device. Complications of procedures are considered not related if the said procedures would have been applied to the patients also in the absence of investigational device use/application.  
In some cases, the event may be not adequately assessed because information is insufficient or contradictory and/or the data cannot be verified or supplemented. The Sponsor and the Investigators will make the maximum effort to define and categorize the event and avoid these situations. Where the Sponsor remains uncertain about classifying the serious event, it should not exclude the relatedness and classify the event as "possible".
investigational plan "multi-center open-labeled nonrandomized
9.3.3 severity

The severity of the AEs will be assessed according to the NCI CTCAE version 4.0 (44) (Appendix 2). If NCI CTCAE grading does not exist for an AE, the severity of mild, moderate, severe, life-threatening and death, corresponding to grades 1 - 5, will be used:  
| Grade                                                                                               | Severity                                                                                                    |    |           |             |     |     |             |                   |
|-----------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|----|-----------|-------------|-----|-----|-------------|-------------------|
| 1                                                                                                   | Mild; asymptomatic or mild symptoms; clinical or diagnostic observations  only; intervention not indicated. |    |           |             |     |     |             |                   |
| 2                                                                                                   | Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental activities of daily living (ADL) a .                                                                                                             |    |           |             |     |     |             |                   |
| 3                                                                                                   | Severe                                                                                                      | or | medically | significant | but | not | immediately | life-threatening; |
| hospitalization or prolongation of hospitalization indicated; disabling; limiting  self care ADLb,c |                                                                                                             |    |           |             |     |     |             |                   |
| 4                                                                                                   | Life-threatening consequences; urgent intervention indicated d .                                            |    |           |             |     |     |             |                   |
| 5                                                                                                   | Death related to AE d .                                                                                     |    |           |             |     |     |             |                   |
| Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone,  |                                                                                                             |    |           |             |     |     |             |                   |  
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. If an event is assessed as "medically significant" it must be reported as a SAE. Grade 5 AE must be reported as a SAE.
investigational plan "multi-center open-labeled nonrandomized
9.4 collecting and reporting of

The investigator must record all AEs, whether or not related to the use of the study medical device in the CRF.  
The occurrence of AEs should be sought by questioning of the patient during the screening process after signing informed consent and at each visit during the study. AEs also may be detected when they are volunteered by the patient during the screening process or between visits, or through physical examination, laboratory test, or other assessments.  
As far as possible, the following information will be collected for each AE in the CRF:  
The severity grade according to the NCI CTCAE version 4.0 (Appendix 2).  
Its duration (start and end dates, or ongoing at end of study).  
Its suspected relationship to the investigational device (VORTX Rx®)
Whether any medication or therapy was given due to the AE. If a concomitant medication or non-drug therapy is given, this action should be recorded on the eCRF.  
Whether it is serious.  
Its outcome.  
Once an AE is detected, it should be followed until its resolution or until it is judged to be stabilized; an assessment should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the medical device, the interventions required to treat it, and the outcome.
investigational plan "multi-center open-labeled nonrandomized
9.4.1 reporting of serious adverse

Every SAE, regardless of suspected causality, occurring after ablation initiation, will be reported to the Sponsor within 24 hours of learning of its occurrence. The new findings/updates to the already reported SAE will be notified as follow-up to the original episode within 24 hours of the investigator after awareness by the investigator. Information about all SAEs will be collected and recorded on the SAE Form where all applicable sections of the form must be completed. The investigator will assess and record the relationship of each SAE to the study medical device or the procedure, complete the SAE Form in English, and send the completed, signed form by fax within 24 hours to the CRO Dynamic Science S.L. (Fax: +34 914561126), who will communicate the SAEs to the Sponsor. The original copy of the SAE Form and the fax confirmation sheet will be kept with the eCRF documentation at the study site.
investigational plan "multi-center open-labeled nonrandomized
9.4.1.2 report by the sponsor

SAE reporting to the National Competent Authorities will be conducted according to the MEDDEV 2.7/3 revision 3 (May 2015) guideline for SAEs reporting in clinical investigations with medical devices in line with the requirements of Annex 7 of Directive 90/385/EEC and Annex X
of Directive 93/42/EEC, as amended by Directive 2007/47/EC, and the Circular 07/2004 regulating clinical investigations with medical devices. The sponsor will report all SAEs to Spanish Agency of Medicines and Medical Devices (Agencia Española de Medicamentos y Productos Sanitarios - AEMPS acronym in Spanish) and to the applicable CEIm. The Sponsor will notify the AEMPS of all SAEs experienced since commencement of the procedure, regardless of suspected causal relationship no later than 7 days after occurrence.  
For SAEs which indicate an imminent risk of death, serious injury, or serious illness, that requires prompt remedial action for other patients/subjects, users or other persons* or a new finding to it, the SAE reporting to the AEMPS will be performed immediately, but not later than 2 calendar days after awareness by sponsor of a new reportable event or of new information in relation with an already reported event. The completed SAE report form will be sent by email in Excel to the AEMPS, or an equivalent format which allows using the inserted filters. The SAE reporting will be updated and transmitted to the AEMPS each time a new reportable event or a new finding/update to an already reported event is to be reported. More detailed information will be provided on request of the AEMPS, if so requested by using the individual reporting form. The Sponsor shall identify the new/updated information in the status column of the tabular form as: a = added = new reportable event; m = modified =new finding/update to an already reported event; u = unchanged Changes in a line should be highlighted in bold and/or color in the respective column.  
* This includes: A) events that are of significant and unexpected nature such that they become alarming as a potential public health hazard, e.g. human immunodeficiency virus (HIV) or Creutzfeldt-Jacob Disease (CJD). These concerns may be identified by either the NCA or the manufacturer. B) the possibility of multiple deaths occurring at short intervals.
investigational plan "multi-center open-labeled nonrandomized
9.5 data and safety monitoring

The Data and Safety Monitoring Board (DSMB) is an independent group of experts that advises study team, sponsor and the study investigators. The members of the DSMB serve in an individual capacity and provide their expertise and recommendations. The members of the DSMB will be experts who are independent from the Sponsor. This board will convene at regular intervals to review any SAEs and device malfunctions that occur during the study. The DSMB will serve as a data monitor and make recommendations based on the data regarding the safety of patients utilizing a risk/benefit ratio in relation to the study and ablation outcomes. The DSMB will make recommendations to the study sponsor regarding the safety of the study, and whether the study should continue under the current protocol, under a revised protocol or be stopped due to safety concerns. The DSMB may also recommend halting enrollment to perform a detailed review of a device or patient situation/AE that is unexpected or in a higher frequency than has previously been reported. Patient safety is the highest priority for this study, involving this device and procedure. A DSMB charter will be developed, which will outline the guidelines the DSMB will use to review and make recommendations to the Sponsor regarding study continuation. DSMB Composition: The composition DSMB for this study will be included in the DSMB
Charter.  
DSMB meetings/review frequency: It is anticipated the DSMB will meet monthly for this study; however, meetings may be postponed or cancelled due to lack of new data. The DSMB will review the research protocol and plans for data and safety monitoring. Once monthly, the DSMB will review the study's data manager's report that will include the following information:
The number of participants consented for the study The reasons for withdrawal (if any) from the study Any safety concerns revealed during the course of the study Summary of AEs and serious AEs Summary of UADEs The current, approved consent form Any material presented to the DSMB will be presented in a way to preserve patient confidentiality. The DSMB will also review the investigator's summary of any new data or evidence that might alter the risk/benefit ratio for participating in the study. After reviewing this information, the DSMB will hold a meeting with the Study Sponsor and report its summary of any serious and unexpected AEs, UADEs, or other unanticipated problems that involve risk to study participants, and whether these appear related to the study-based interventions. Minutes of such meeting will be prepared to document the DSMB's communication to the study sponsor.  
The membership of the DSMB should reflect the disciplines and medical specialties necessary to interpret the data from the clinical study and to fully evaluate participant safety. The number of DSMB members, will be based on the complexity in design and analysis, and potential level of risk but generally consists of three to seven members with desired participation from:
Expert(s) in the clinical aspects of the disease/patient population being studied; A biostatistician; and, Investigators with expertise in current clinical study conduct and methodology Ad hoc specialists may be invited to participate as non-voting members at any time if additional expertise is desired. Staff without direct involvement in study implementation and who meet other membership criteria may participate as *ex officio*, non-voting members. Staff serving in these positions must have a current confidential financial disclosure report on file. Representatives of the sponsor (industry) of the test device or any other individual with vested interests in the outcome of the study are not eligible to serve on the DSMB although they may attend open sessions of the DSMB meetings. No member of the DSMB should have direct involvement in the conduct of the study. There will be regular, ongoing communication between the study sponsor, the investigator and the DSMB. The investigator will take responsibility for reporting any serious and unexpected AEs or other unanticipated study problems to the study sponsor, and, where required, the Competent Authority. A copy of each report will be sent to the DSMB. Actions taken by the ethics committee in response to AE reports will be immediately reported to the DSMB,
investigators and study sponsor, which will review all SAEs, as they arise.
investigational plan "multi-center open-labeled nonrandomized
10 statistical methods and data

No formal statistical power calculations to determine sample size is performed for this study due to the nature of this study design and patient population.  
Due to the nature of this study in which the investigational device will be used for the first time for soft tissue ablation of liver tumors in humans, the approximate number of patients planned to be included in this study is 10.
investigational plan "multi-center open-labeled nonrandomized
10.2 overall considerations

Upon completion of the study, after the data for the final study patient have been recorded, and once all possible data discrepancies have been resolved, the study database will be locked and transferred to the person responsible for statistical analysis. A detailed statistical analysis plan will be prepared at the appropriate time, which will be approved by the sponsor, to guide the analysis of the data and justify any change in the original plan.  
A general description will be given of the variables included in the study and non-parametric tests will be performed if applicable. There are no plans to allocate unavailable data, which will simply be described as missing data. The statistical analysis of the study data will be carried by the biometrics department of Dynamic Science S.L.  
No interim analyses are planned.
investigational plan "multi-center open-labeled nonrandomized
10.3analysis sets 10.3.1 full analysis

The full analysis set includes all patients who have undergone an ablation with the investigational device. The full analysis set will be used for all listings of raw data.
investigational plan "multi-center open-labeled nonrandomized
10.3.2 safety population

The study population that will be included in the safety analysis consist of all patients who have undergone an ablation with the investigational device.
investigational plan "multi-center open-labeled nonrandomized
10.3.3 technical performance population

The technical performance population set includes all patients who have undergone an ablation with the investigational device and have an assessment of technical performance.
investigational plan "multi-center open-labeled nonrandomized
10.4 patient demographics/other baseline characteristics

Demographic and other baseline data will be summarized descriptively for the full analysis set.
investigational plan "multi-center open-labeled nonrandomized
10.5 primary objective/endpoint

The primary objective of the study is to evaluate the acute technical performance of the VORTX
Rx® medical device for the ablation of primary and metastatic liver tumors. The ability of the investigational device to create an ablation zone that correspond to the PAV (a threedimensional volume defined by the investigator using the VORTX Rx® in the planning phase of the software workflow) will be assessed by multi-dimensional measurement of the 1 day postprocedure ablation zone and accompanied by general radiological findings characterized
(qualitatively) in radiology report from a central radiologist reader applying The International Working Group Image-guided Tumor Ablation guidance (42, 45). The acute technical success of up to 3 separate tumor ablations will be assessed in each patient.  
The number of targeted tumors in whom technical success is achieved (ablation zone corresponds to PAV) will be divided by the number of targeted tumors in which the ablation has been initiated with the investigational device to calculate technical success percentage.
investigational plan "multi-center open-labeled nonrandomized
10.6 secondary objectives

Safety profile of the investigational medical device will be assessed on the basis of all AEs
(serious and non-serious, and probably or definitively related to the medical device)
experienced during the procedure conducted with this medical device and all observed and volunteered AEs and abnormal findings on physical examination, vital signs, laboratory and imaging tests throughout the study.
The safety analysis will be performed in the "safety population" which includes all patients who have undergone an ablation with the VORTX Rx® medical device.  
All AEs recorded during the study will be listed and summarized. All SAEs will be listed by patients. Any other safety information will be listed and tabulated as appropriate. This includes analysis of all AE and SAEs throughout the study, physical examinations, changes in vital signs, ECOG performance status, laboratory values, and ECG. Summary tables for AEs should include only AEs that started or worsened during the ablation and post-ablation follow-up period (2 months).  
The incidence of ablation-emergent AEs (new or worsening since ablation initiation) will be summarized by system organ class and or preferred term, severity (based on CTCAE
version 4.0 grades), type of AE, whether they were SAEs or not, and relation to the medical device under study. The incidence of the following AEs, if definitively related to the study medical device, will be evaluated:
1. Major bleeding that requires transfusion within 48 hours 2. Visceral perforation (bowel or stomach)
3. Major biliary duct injury 4. Death The safety profile of the study will be deemed favorable if there are:
No deaths due to the ablation, and  
No deaths from visceral perforation (bowel or stomach), and 20% or lower incidence of major bleeding requiring transfusion within 48h, and 20% or lower incidence major bile duct injury.  
To assess the local tumor progression.  
o Assessment of the ablation zone of each tumor will be conducted by a centralreader radiologist based on local tumor progression according to the International Working Group Image-guided Tumor Ablation (42, 45) (Appendix 3) at 1-week, 1 month and 2 months post-ablation.  
To assess the involution of the ablation zone.  
o The size of each tumor ablation zone on MRI and optional CT will be captured at each post-ablation follow up visit will be assessed and compared at 1-week, 1 month and 2 months post-ablation.  
To assess liver panel post-ablation.  
o The change in the levels of the liver function parameters (AST, ALT, alkaline phosphatase, albumin, bilirubin, GGT, PT and INR) will be calculated from baseline to the post-procedure evaluation performed 24 hours post-ablation and the followup visits performed 1 week, and 1 and 2 months post-procedure.  
To evaluate immunological response of ablation o The change in the levels from immune tests (Immune tests including: CD3+, CD4+,
CD8+, CD45+, CD16+, CD56+ and CD19+, CRP, complement C3, C4 and CH50, immunoglobulins (IgG, IgM, IgA)), IL-6, and tumor biomarkers (CEA, AFP, Cancer Antigens CA15-3 (Breast Cancer) and CA 19-9 (Pancreatic Cancer) (50, 51) will be calculated from baseline to the post-procedure evaluation performed 24 hours postprocedure and the follow-up visits performed 1 week, and 1 and 2 months postprocedure.  
To evaluate patient quality of life of patient's post-procedure.  
o For the analysis of change of quality of life, the descriptive statistics of the score of the dimensions and the total score of the QLQ-C30 questionnaire will be performed, and the change from the screening to the visits at 1 and 2 months post-procedure will be calculated.  
o QLQ-C30 scores will be generated according to the EORTC Scoring Manual
(Appendix 4). These scores vary from 0 (worst) to 100 (best) for the GHS and functional scales, and from 0 (best) to 100 (worst) for symptomatic scales.  
To assess pain and analgesic requirements post-procedure.  
o The VAS scale score will be calculated 24 hours and 1 week post-procedure and the change in pain score will be analyzed (Appendix 5).  
o The number of patients requiring analgesics 24 hours and 1 week post-procedure will be calculated and compared.
investigational plan "multi-center open-labeled nonrandomized
11 ethical considerations 11.1regulatory and

This clinical trial will be conducted in accordance with the protocol, the principles established in the current revised version of the Declaration of Helsinki (Fortaleza, Brazil; October 2013), and in accordance with applicable regulatory requirements for investigations with medical devices, in particular the Circular 7/2004 of the AEMPS regulating the clinical investigations with medical devices. By signing the protocol, the investigator agrees to adhere to the instructions and procedures described in the protocol and thereby to adhere to the principles of good clinical practice for medical device trials that it conforms to. The sponsor will submit the pertinent documentation to the CEIm. The study may not be started until approval by the CEIm and the AEMPS has been obtained. Handling, communication and transfer of the personal data for all the participating subjects will comply with the stipulations of the Regulation (EU) 2016/679 on Personal Data Protection. The investigator and study data will be entered and processed in a file owned by the sponsor, which will be held by Dynamic Science, in accordance with the aforementioned Organic Law. The study staff involved in the conduct of this trial will be appropriately qualified education, training and experience to perform the assigned tasks.
investigational plan "multi-center open-labeled nonrandomized
11.2informed consent procedures

Each subject who is asked to participate in the study will be informed about the same both orally and in writing providing them with a document called "Patient Information Sheet", which will contain the necessary relevant information for the patient in a form that is entirely legible and comprehensible to decide if he/she wishes to participate in the trial (Appendix 1). It is the responsibility of the investigator to obtain informed consent from each patient participating in the study after explaining the objectives, methods, potential benefits and risks of the study deriving from their participation in the study, the confidentiality of personal data and the contact details for the doctor responsible for the study. Consent must be obtained before performing any study-specific procedure. Each patient should be explained in a clear and unequivocal manner that he/she is free to refuse to participate in the study and that he/she may withdraw his/her consent at any time for any reason without penalty or refusal of the best treatment as the investigator's discretion. The investigators must keep the signed informed consent in the study file and it must be documented in the eCRF and in the patients' medical records. The investigator will obtain the subject's informed consent (preferably in writing, or if not feasible, orally before witnesses independent of the research team). In addition, the subject participating in the study must be given a copy of the informed consent.
investigational plan "multi-center open-labeled nonrandomized
11.3confidentiality

The information disclosed and obtained during this study will be considered confidential and must be treated as such at all times.  
The study data and materials may not be disclosed in part or in full by the investigator or his/her staff to any unauthorized person without the prior formal written consent of the sponsor. All materials, information (oral or written) and unpublished documentation provided to the investigators, including this protocol and the CRFs (electronic and/or paper), and all documents generated during the study and the database, will be considered the property of the sponsor, and will be protected from non-permitted uses by persons unrelated to the research and, therefore, will be considered strictly confidential and will not be disclosed to third parties except for those specified in the subsequent paragraph. The investigator and the institution will permit direct access to the source data and documents for the performance of monitoring, auditing, review by the medicinal product research ethics committee, and trial inspection by the health authorities. This access will be restricted to the sponsor, monitor, study doctors and their research staff, the AEMPS, the competent health authorities of the autonomous communities, the CEIm, and the sponsor or personnel authorized by the sponsor, when necessary to verify the study data and procedures, but always maintaining their confidentiality in accordance to current legislation.  
Only medical history data that are related to the study will be subject to verification. This verification will be done to the extent possible in the presence of the principal investigator/coinvestigators, and the confidentiality of all personal data of the subjects participating in the clinical trial will be maintained at all times in accordance with the Regulation (EU) 2016/679 on Personal Data Protection. Handling, communication and transfer of the personal data for all the participating subjects will comply with the stipulations of the Regulation (EU) 2016/679 on Personal Data Protection. The investigator and study data will be entered and processed in a file owned by the sponsor, which will be held by Dynamic Science, in accordance with the aforementioned Organic Law.
investigational plan "multi-center open-labeled nonrandomized
12 practical considerations 12.1archiving

For the purpose of the clinical trial, a file will be generated with all the study documentation, including the protocol, CRF, signed informed consents, reports of SAEs and authorizations of National Competent Authorities. One copy of which will be kept by the investigator at his/her site (investigator file) and another by the sponsor (sponsor file). The content of these files will comply with the requirements for study documentation in applicable legislation.  
The study documentation will be kept for the time required by currently applicable legislation.
investigational plan "multi-center open-labeled nonrandomized
12.2 source documents

The CRF will be considered the source document for the VAS scale for pain assessment and the quality of life questionnaire QLQ-C30, since these specific study procedures are not performed under clinical practice conditions.
investigational plan "multi-center open-labeled nonrandomized
access to source documents

The study will be monitored by regular visits and phone calls to the investigator. During visits to the study site, the monitor must review the original patient records, medication records and document storage. The monitor must also evaluate the study procedures and discuss any possible problems with the investigator. During the course of the study, auditing visits to the participating sites may be performed.  
In compliance with applicable regulations, the investigator and his/her team as well as the study site are required to permit authorized representatives of the study sponsor, regulatory agencies and the CEIm direct access for review of the data/documents of the patients' original medical records for verification of the study procedures and study-related data. This direct access includes examination, analysis, verification and reproduction of any record or report that is important for evaluation of the study. The investigator is obliged to inform and obtain consent from the subject to permit access by designated representative to the subject's study-related records without violating the confidentiality of the subject.
investigational plan "multi-center open-labeled nonrandomized
13 quality control 13.1study monitoring

The accuracy of the data recorded in the eCRF will be verified by study monitor by verifying the recorded data. During the study, monitoring visits will be performed to ensure the study complies with all aspects of the protocol, good clinical practice (GCP) guidelines and applicable legislation. The source documents (original documents, data and records) will be reviewed to verify the information recorded in the eCRFs. The investigator and the site will ensure the sponsor or its representative (including the monitor), the CEIm and the health authorities have access to the study documents. This access includes the investigator file, eCRF, patient information sheet and informed consent, medical histories of the subjects and other source documents. It is important that the investigator and study staff be available during the monitoring visits and devotes sufficient time to the process.
investigational plan "multi-center open-labeled nonrandomized
14 funding

All financial aspects related to the clinical trial will be specified in a contract between the sponsor and the sites where the trial is to be conducted. The financial budget of the study will be made available to the CEim for its evaluation. The sponsor will fund the study in accordance with the guidelines of the present protocol. This funding includes all materials necessary to conduct the study; the cost of the authorization and control processes with the research and health authorities; design, maintenance and management of the database; and statistical analysis of the information generated. In any event, the funding shall be independent of the results of the study.  
As required by current legislation and in particular by the Circular 07/2004, the sponsor has taken out an insurance policy with the company Chubb European Group Limited, with an address at Paseo de la Castellana 141, 6 Planta 28046 Madrid, España and with policy number ESCAIA21218, which covers the liabilities of the sponsor/principal investigator, the research staff and the sites where the clinical trial is conducted, in the event of any damage or injury to the health of the patient resulting from this research, conducted strictly in accordance with both the scientific protocol and applicable law in Spain and professional standards, during the conduct of the study and for one year following termination of the study, unless otherwise proven.
investigational plan "multi-center open-labeled nonrandomized
15 publication guidelines

All information related to the study is considered confidential and property of the sponsor until its publication. It must not be revealed to others without prior written consent from the sponsor. Once the study has been completed and the statistical report has been performed, the sponsor, in conjunction with the investigators, will prepare the final study report, which will be submitted to the investigators, the research ethics committees, the AEMPS and the health authorities, if so requested. This final report will be the basis for the preparation of the manuscripts that are desired to be published in medical journals. The sponsor is obliged to publish the results, whether positive or negative, in scientific journals, meetings and/or congresses, before being disclosed to the non-healthcare public, indicating the funding obtained for conduct of the trial and ensuring at all times the anonymity of the participating subjects. The results or conclusions of this study will be reported at scientific congresses and published in scientific journals. The investigator agrees to maintain this information in strict confidence, and will not use it for any other purpose without the written authorization of the sponsor.
investigational plan "multi-center open-labeled nonrandomized
16 references

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3. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208-36. Epub 2005/10/27. 4. Ferenci P, Fried M, Labrecque D, Bruix J, Sherman M, Omata M, et al. Hepatocellular carcinoma (HCC): a global perspective. Journal of clinical gastroenterology. 2010;44(4):239-45. Epub 2010/03/11.  
5. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. International journal of cancer. 2001;94(2):153-6. Epub 2001/10/23.  
6. Parkin DM. Global cancer statistics in the year 2000. The Lancet Oncology. 2001;2(9):53343. Epub 2002/03/22.  
7. Ananthakrishnan A, Gogineni V, Saeian K. Epidemiology of primary and secondary liver cancers. Seminars in interventional radiology. 2006;23(1):47-63. Epub 2006/03/01. 8. Wyld L, Gutteridge E, Pinder SE, James JJ, Chan SY, Cheung KL, et al. Prognostic factors for patients with hepatic metastases from breast cancer. Br J Cancer. 2003;89(2):284-90. Epub 2003/07/17. 9. Ouyang H, Wang P, Meng Z, Chen Z, Yu E, Jin H, et al. Multimodality treatment of pancreatic cancer with liver metastases using chemotherapy, radiation therapy, and/or Chinese herbal medicine. Pancreas. 2011;40(1):120-5. Epub 2010/08/05. 10. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(22):3677-83. Epub 2009/05/28. 11. Wicherts DA, de Haas RJ, Adam R. Bringing unresectable liver disease to resection with curative intent. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2007;33 Suppl 2:S42-51.  
Epub 2007/11/06. 12. Zakaria S, Donohue JH, Que FG, Farnell MB, Schleck CD, Ilstrup DM, et al. Hepatic resection for colorectal metastases: value for risk scoring systems? Annals of surgery. 2007;246(2):183-91. Epub 2007/08/02.  
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investigational plan "multi-center open-labeled nonrandomized
17 appendices

APPENDIX 1. Patient information sheet and informed consent form (ICF)
Attached as separate documents.
appendix 5. vas for pain
appendix 2. nci-ctcae (version 4.0)

Attached as a separate document.  
APPENDIX 6. Eastern Cooperative Oncology Group performance status  
| Grade                      | Performance status                                                                                                                                          |
|----------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0                          | Fully active, able to carry on all pre-disease performance without restriction.                                                                             |
| 1                          | Restricted in physically strenuous activity but ambulatory and able to carry out work of a  light or sedentary nature, e.g., light house work, office work. |
| 2                          | Ambulatory and capable of all self care but unable to carry out any work activities. Up and  about more than 50% of waking hours.                           |
| 3                          | Capable of only limited self care, confined to bed or chair more than 50% of waking hours.                                                                  |
| 4                          | Completely disabled. Cannot carry on any self care. Totally confined to bed or chair.                                                                       |
| 5                          | Dead.                                                                                                                                                       |
| Source: Oken et al (1982). |                                                                                                                                                             |
appendix 5. vas for pain
appendix 7. american society of

| Current definitions (NO CHANGE) and Examples (NEW)                                                                                                                                                    |                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                               |                    |      |         |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|------|---------|
| ASA PS                                                                                                                                                                                                | Definition                                                                                                                                                                                                                    | Examples, including, but not                                                                                                                                                                                                                                                                                                                                                                                                                  |                    |      |         |
| Classification                                                                                                                                                                                        | limited to:                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                               |                    |      |         |
| ASA I                                                                                                                                                                                                 | A normal healthy patient                                                                                                                                                                                                      | Healthy,                                                                                                                                                                                                                                                                                                                                                                                                                                      | non-smoking,       | no   | or      |
| minimal alcohol use                                                                                                                                                                                   |                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                               |                    |      |         |
| ASA II                                                                                                                                                                                                | A patient with mild systemic disease                                                                                                                                                                                          | Mild                                                                                                                                                                                                                                                                                                                                                                                                                                          | diseases           | only | without |
| substantive functional limitations.  Examples include (but not limited  to): current smoker, social alcohol  drinker, pregnancy, obesity (30 <  BMI < 40), well-controlled  DM/HTN, mild lung disease |                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                               |                    |      |         |
| ASA III                                                                                                                                                                                               | A patient with severe systemic disease                                                                                                                                                                                        | Substantive functional limitations;  One or more moderate to severe  diseases. Examples include (but  not limited to): poorly controlled  DM or HTN, COPD, morbid  obesity (BMI ≥40), active hepatitis,  alcohol dependence or abuse,  implanted pacemaker, moderate  reduction of ejection fraction,  ESRD undergoing regularly  scheduled dialysis, premature  infant PCA < 60 weeks, history  (>3 months) of MI, CVA, TIA, or  CAD/stents. |                    |      |         |
| ASA IV                                                                                                                                                                                                | A patient with severe systemic disease                                                                                                                                                                                        | Examples include (but not limited                                                                                                                                                                                                                                                                                                                                                                                                             |                    |      |         |
| that is a constant threat to life                                                                                                                                                                     | to): recent (< 3 months) MI, CVA,  TIA, or CAD/stents, ongoing  cardiac ischemia or severe valve  dysfunction, severe reduction of  ejection fraction, sepsis, DIC, ARD  or ESRD not undergoing regularly  scheduled dialysis |                                                                                                                                                                                                                                                                                                                                                                                                                                               |                    |      |         |
| ASA V                                                                                                                                                                                                 | A moribund patient who is not expected                                                                                                                                                                                        | Examples include (but not limited                                                                                                                                                                                                                                                                                                                                                                                                             |                    |      |         |
| to survive without the operation                                                                                                                                                                      | to):                                                                                                                                                                                                                          | ruptured                                                                                                                                                                                                                                                                                                                                                                                                                                      | abdominal/thoracic |      |         |
| aneurysm,                                                                                                                                                                                             | massive                                                                                                                                                                                                                       | trauma,                                                                                                                                                                                                                                                                                                                                                                                                                                       |                    |      |         |
| intracranial bleed with mass effect,  ischemic bowel in the face of  significant cardiac pathology or  multiple organ/system dysfunction                                                              |                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                               |                    |      |         |
| ASA VI                                                                                                                                                                                                | A declared brain-dead patient whose  organs are being removed for donor  purposes                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                               |                    |      |         |
| *The addition of "E" denotes Emergency surgery: (An emergency is defined as existing when                                                                                                             |                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                               |                    |      |         |  
Last approved by the ASA House of Delegates on October 15, 2014