HCLS/SWAT4LS2012/Hackathon/TrialProtocols

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RDF and SPARQL against CDA Patient Documents

  • XML2RDF Transformation of CDA Patient Documents
  • SPARQL Queries Against CDA Patient Documents
  • Summary
    • We have converted 215 CDA docuemnts from XML to RDF and loaded them into a 4store instance and started a SPARQL endpoint. XML Reuse Technology is handy for converting CDA documents in XML to RDF.
    • With RDF representation of CDA documents, we were able to define SPARQL queries to identify patients with specific eligibility criteria.
      • A simple criterion is to identify patients with gender "Male" or "Female". As the results, out of 215 patients, 110 of them are female and 105 of them are male.
      • We also tried to leverage SNOMED CT and LOINC codes to identify patients. For example,
        • we were able to identify patients whose records contain information about "drug allergy" using SNOMED CT code "416098002".
        • or to identify patients whose records contain information about "History of medication use" using LOINC code "10160-0".

Cervix/Embrace

Inclusion criteria

  • Cancer of the uterine cervix considered suitable for curative treatment with definitive radio-(chemo)therapy including MRI guided BT
 diagnose: sn:123841004 (uterine cervical carcinoma)
 prescribe: sn:228859002 (radiotherapy) | sn:77781 (BT)
  • Positive biopsy showing squamous-cell carcinoma, adenocarcinoma or adeno-squamous cell carcinoma of the uterine cervix.
 28899001: squamous-cell carcinoma
 35917007: adenocarcinoma - no-subtype

...


  • Staging according to FIGO and TNM guidelines
  • MRI of pelvis at diagnosis is performed
  • MRI, CT or PET-CT of the retroperitoneal space and abdomen at diagnosis is performed
  • MRI with the applicator in place at the time of (first) BT will be performed
  • Para-aortic metastatic nodes below L1-L2 are allowed
  • Patient informed consent

Exclusion criteria

  • Other primary malignancies except carcinoma in situ of the cervix and basal cell carcinoma of the skin
  • Metastatic disease beyond para-aortic region (L1-L2)
  • Previous pelvic or abdominal radiotherapy
  • Previous total or partial hysterectomy
  • Combination of preoperative radiotherapy with surgery
  • Patients receiving BT only
  • Patients receiving EBRT only
  • Patients receiving neoadjuvant chemotherapy
  • Contra indications to MRI
  • Contra indications to BT

Version 17-01-2008 13  Active infection or severe medical condition endangering treatment delivery  Pregnant, lactating or childbearing potential without adequate contraception

closed/Botmeta's/Botstudie.doc

4.0 STUDY POPULATION Patients with painful bone metastases after previous palliative radiotherapy to the diseased bone will be included in this study. The initial radiation dose to the extremities/ribs can be a single fraction of 6, 7 or 8 Gy, 18 Gy in 4 fractions, 20 Gy in 5 fractions, 24 Gy in 6 fractions, 27 Gy in 8 fractions or 30 Gy in 10 fractions. The initial radiation dose to metastases in the spine and pelvis can be a single fraction of 6, 7 or 8 Gy, 18 Gy in 4 fractions or 20 Gy in 5 fractions. Concerns over re-irradiation to the spine or pelvis encompassing small or large bowel and/or the rectum previously treated with 24 Gy in 6 fractions, 27 Gy in 8 fractions and 30 Gy in 10 fractions preclude these groups of patients from this study. Initial doses of 24 Gy in 6 fractions, 27 Gy in 8 fractions or 30 Gy in 10 fractions to the acetabulum/hip and proximal femur are eligible as long as the medial field border of the initial treatment did not cross midline (pubic symphysis). Re-irradiation may be offered for the following indications: Relapse of pain, after complete or partial response to previous (initial) palliative radiotherapy Further reduction of pain is desired in partial responders No response or progression of pain (without any response) since initial treatment

4.1 Eligibility Criteria There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. Questions about eligibility criteria should be addressed PRIOR to calling for randomization. The eligibility criteria for this study have been carefully considered. Eligibility criteria are standards used to ensure that patients who enter this study are medically appropriate candidates for this therapy. For the safety of the patients, as well as to ensure that the results of this study can be useful for making treatment decisions regarding other patients with similar diseases, it is important that no exceptions be made to these criteria for admission to the study. Patients must fulfill all of the following criteria to be eligible for admission to the study: 4.1.1 Patient must be 18 years of age or older at the time of randomization. 4.1.2 Patient must have histologically or cytologically proven malignancy. Histological diagnosis may be established from needle biopsy, bone marrow biopsy, cytology, or a surgical biopsy or resection. All malignant histologies/cytologies are eligible. 4.1.3 Plain radiographs, radionuclide bone scans, CT scans and/or magnetic resonance imaging confirm the presence of bone metastases corresponding to clinically painful area. 4.1.4 Patient has a worst pain score of > 2/10 as reported using the baseline Brief Pain Inventory completed by the patient prior to randomization. 4.1.5 There is no plan to make an immediate change in the analgesic regimen on the day of randomization. 4.1.6 Karnofsky Performance Status > 50 within one week prior to randomization. 4.1.7 The interval between the last fraction of the initial radiation and the date of randomization in this study is > 4 weeks. 4.1.8 Initial radiation treatment field is reproducible for re-irradiation. 4.1.9 Pain is arising from the previously irradiated metastasis(es) and not from progressive disease in the adjoining or remote areas. 4.1.10 Site of pain considered for palliative radiotherapy must be encompassed by the same or smaller treatment field/portal as initial treatment. 4.1.11 Canadian, Dutch and RTOG centres only: Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaire in English, French, Spanish or Dutch. The baseline assessment must already have been completed. Inability (illiteracy in English, French, Spanish or Dutch, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible. 4.1.12 For Canadian patients: Patient consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements. It will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG Study Coordinator that such clearance has been obtained, before the trial can commence in that centre. Because of differing requirements, a standard consent form for the trial will not be provided but a sample form is given in Appendix XIII. A copy of the initial full board REB approval and approved consent form must be sent to the central office. The patient must sign the consent form prior to randomization or registration. Please note that the consent form for this study must contain a statement which gives permission for the NCIC CTG and monitoring agencies to review patient records. For cooperative group patients: Patient consent and centre regulatory compliance must be obtained according to the policies mandated by the responsible cooperative group and/or national regulations. 4.1.13 Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. 4.1.14 In accordance with NCIC CTG policy, treatment must begin within 4 weeks of randomization. 4.1.15 If the site followed for this study is in the ribs or extremities, the initial radiation was given in a single fraction of 6, 7 or 8 Gy, 18 Gy in 4 fractions, 20 Gy in 5 fractions, 24 Gy in 6 fractions, 27 Gy in 8 fractions or 30 Gy in 10 fractions. If the site followed for this study is the acetabulum/hip and/or the proximal femur without the medial field border crossing midline pubic symphysis), the initial radiation was given in a single fraction of 6, 7 or 8 Gy, 18 Gy in 4 fractions, 20 Gy in 5 fractions, 24 Gy in 6 fractions, 27 Gy in 8 fractions or 30 Gy in 10 fractions. If the site followed for this study is the spine or another area of the pelvis that is not excluded from the study (see 4.2.11), the initial radiation was given as a single fraction of 6, 7 or 8 Gy, 18 Gy in 4 fractions or 20 Gy in 5 fractions.

4.2 Ineligibility Criteria Patients who fulfill any of the following criteria are not eligible for admission to the study: 4.2.1 Clinical or radiological evidence of spinal cord compression at the time of assessment for this study. 4.2.2 Clinical or radiological evidence of pathological fractures of extremities in the area to be re-irradiated. 4.2.3 Radiological evidence of high-risk lesions for pathological fractures in the extremities (lytic lesions > 3 cm or > 50% cortical erosion of bone diameter) and candidate for surgical intervention. Patients who are NOT surgical candidates are eligible for this study. 4.2.4 The treatment area has received prior palliative surgery. 4.2.5 There is planned surgical intervention on the treated bone. 4.2.6 Treatment field of initial radiation volume has to be enlarged/modified to accommodate symptomatic disease not previously irradiated, or to provide adequate treatment margin. 4.2.7 Systemic radiotherapy (Sr-89) has been received within 30 days prior to randomization. 4.2.8 Patient has received half body irradiation including the current re-irradiation field within 30 days prior to randomization. 4.2.9 Current site has already had 2 or more courses of radiation. 4.2.10 The patient has been previously admitted to the study. 4.2.11 The patient has been previously treated to the spine or any part of the pelvis encompassing small or large bowel and/or the rectum with 24 Gy in 6 fractions, 27 Gy in 8 fractions or 30 Gy in 10 fractions.

CZS/CATNON.doc

3 Patient selection criteria

All patients are initially registered into the trial as soon as possible after surgery. After this point, material must be sent for 1p/19q analysis and MGMT promoter methylation assay. This should again be done as soon as possible. Patients can only be randomized into the trial within 8 days from the start of radiotherapy; at this time, all baseline requirements for the study must have been fulfilled.

3.1 At the time of registration Histologically confirmed newly diagnosed anaplastic oligodendroglioma, anaplastic oligoastrocytoma or anaplastic astrocytoma by local diagnosis Availability of tumor material for central 1p/19q assessment, central MGMT promoter methylation assessment and central pathology review. Previous surgery for a low grade tumor is allowed, provided histological confirmation of an anaplastic tumor is present at the time of progression WHO performance status 0-2 Age ≥ 18 years All patients must use effective contraception if of reproductive potential. Females must not be pregnant or breast feeding Absence of known HIV infection, chronic hepatitis B or hepatitis C infection Absence of any other serious medical condition that can interfere with follow-up Absence of any medical condition which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction) Absence of previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in situ of the cervix and non-melanoma skin cancer. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial No prior chemotherapy (including no treatment with BCNU containing wafers (Gliadel®) No prior radiotherapy to the brain Before patient registration, written informed consent must be obtained, according to ICH/GCP, and national/local regulations.

3.2 Randomization step The combination of : Histologically confirmed newly diagnosed anaplastic oligodendroglioma, anaplastic oligoastrocytoma or anaplastic astrocytoma by local diagnosis AND Absence of combined 1p/19q loss both of which must have been determined by either local testing or central review Availability of tumor material for central 1p/19q assessment, central MGMT promoter methylation assessment and central pathology review WHO performance status 0-2 Age ≥ 18 years Previous surgery for a low grade tumor is allowed, provided histological confirmation of an anaplastic tumor is present at the time of progression Start of radiotherapy within 8 days from randomization Start of radiotherapy within 7 weeks (49 days) from surgery Patients must be on a stable or decreasing dose of steroids for at least two weeks No prior chemotherapy (including no treatment with BCNU containing wafers (Gliadel®) No prior radiotherapy to the brain No concomitant treatment with other anti-cancer agents or with any other experimental agent Adequate hematological, renal and hepatic function according to all of the following laboratory values (to be performed within 14 days prior to randomization): neutrophils greater or equal to 1.5*109 cells/l platelets greater or equal to 100*109 cells/l bilirubin < 1.5 times upper limit of laboratory normal alkaline phosphatase, ASAT and ALAT <2.5 times upper limit of laboratory normal serum creatinine lower than 1.5 times upper limit of laboratory normal All patients must use effective contraception if of reproductive potential. Females must not be pregnant or breast feeding Absence of known HIV infection, chronic hepatitis B or hepatitis C infection Absence of any other serious medical condition that could interfere with follow-up Absence of any medical condition which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction) Absence of previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in situ of te cervix and non-melanoma skin cancer. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Patients can only be randomized in this trial once.

CZS/GBM Elderly.doc

5.0 STUDY POPULATION

Patients 65 years of age or older, with newly diagnosed, histopathologically confirmed, glioblastoma multiforme (WHO grade IV) who have had prior surgery or biopsy at diagnosis and who are not deemed suitable by their treating physician to receive the standard radiotherapy regimen (60Gy/30 fractions over 6 weeks) in combination with temozolomide.

5.1 Eligibility Criteria There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. Questions about eligibility criteria should be addressed PRIOR to randomization. The eligibility criteria for this study have been carefully considered. Eligibility criteria are standards used to ensure that patients who enter this study are medically appropriate candidates for this therapy. For the safety of the patients, as well as to ensure that the results of this study can be useful for making treatment decisions regarding other patients with similar diseases, it is important that no exceptions be made to these criteria for admission to the study. Patients must fulfill all of the following criteria to be eligible for admission to the study:

Histopathologically confirmed newly diagnosed glioblastoma multiforme (GBM, WHO grade IV). The histological diagnosis must have been made after biopsy or neurosurgical tumour resection. Protocol treatment must begin within 6 weeks of initial surgery/biopsy at diagnosis, and no greater than 2 weeks post-randomization. Patient’s age is > 65 years. Patient is not deemed suitable by the treating physician to receive the standard radiotherapy regimen (60Gy/30 fractions over 6 weeks) in combination with temozolomide. ECOG performance status of 0, 1 or 2 (See Appendix II). Patient may have received and continue to receive corticosteroids, but s/he have to be on a stable or decreasing dose for at least 14 days prior to randomization. Patient has not received prior chemotherapy or radiotherapy. Adequate hematological, renal and hepatic functions as defined by the following required laboratory values obtained within 14 days prior to randomization: Absolute granulocyte count (AGC) > 1.5 x 109/L (1,500 cells/mm3) Platelet count > 100x109/L (100,000 cells/mm3) Serum creatinine < 1.5 times the upper limit of normal Total serum bilirubin < 1.5 times the upper limit of normal ALT (SGPT) < 2.5 times the upper limit of normal and/or AST (SGOT) < 2.5 times the upper limit of normal Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French or any other official language into which the questionnaire is required to be translated. The baseline assessment must have already been completed. Inability (illiteracy in English or French, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible. Patient consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements. Because of differing requirements, a standard consent form for the trial will not be provided but a sample form is provided. The patient must sign the consent form prior to randomization. Please note that the consent form for this study must contain a statement which gives permission for the NCIC CTG and monitoring agencies to review patient records (see section 16.4 for further details). Canadian centres only: It will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG Study Coordinator that such clearance has been obtained, before the trial can commence in that centre. A copy of the initial full board REB approval and approved consent form must be sent to the central office. Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. All other investigations (physical exam, biochemistry and hematology tests etc.) as listed in section 6.0 have been performed prior to randomization (with the exception of requests for diagnostic tissue blocks/slides to be used for central pathology review and correlative studies which will be done after randomization).

5.2 Ineligibility Criteria Patients who fulfill any of the following criteria are not eligible for admission to the study: Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for > 5 years. Patients with a serious active infection (such as a wound infection requiring parenteral antibiotics) at the time of randomization or other serious underlying medical conditions that would impair the ability of the patient to receive protocol treatment. Patients with any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol. Patients with known hypersensitivity to temozolomide or compounds with similar chemical composition to temozolomide. Patients who have had treatment with any investigational cancer drug prior to randomization.

CZS/Medullablastoma.doc

Medullablastoma

Informed consent          Arts vraagt de patiënt om mee te doen en geeft informatie          Afhankelijk van de diagnose (uitgebreidheid van de tumor) wordt de patiënt ingedeeld in de standaard risico groep of verhoogd risico groep          Patiënt tekent standaard risico IC of verhoogd risico IC          Arts geeft patiënt door aan DCM (Anita Botterweck, 55886)          Patiëntgegevens invoeren: inclusielijst.xls, WEH3/ CZS/Registratie studies/medullablastoma in adults.          (check of aan inclusieciteria voldaan is)          Meld studiepatiënt bij IKNL aan (geb-datum, geslacht, patisnr, behandeld arts en registratiedatum = IC datum) Registreren          Neem studienr over op CRF’s          Registreer patient in trial agenda: trial nr 122 en arts BB          Aantallen patienten verschijnen alleen in trialoverzicht Toestemmingsverklaring          Origineel toestemmingsverklaring in investigator file; IC ook inscannen. (Origineel in status =vervallen)

CRF’s          DCM checkt volledigheid CRF’s          Kopieën van CRF’s blijven in datfile Maastro clinic          Origineel ingevulde CRF’s opsturen naar IKNL trialbureau (zie adres beneden) Follow-up          Fu formulier invullen volgens schema:          1e jaar elke 3 maanden          2e jaar elke 4 maanden          3e - 5e jaar elke 6 maanden, daarna jaarlijks tot 10 jaar Translation research          Tumormateriaal/ bloed, zie protocol blz 15 en 16

SAE’s Completeer SAE form binnen 24 uur en stuur het op naar IKNL

Trialbureau IKNL (lokatie) Utrecht: c/o huispost F02-162 Postbus 85500, 3508 GA Utrecht Telefoonnr. 088 -755 6286 Faxnr. 088 - 755 5462

CZS/Meningioma-22042.doc

Patients will be registered between surgery and the start of radiotherapy without exceeding 6 weeks however in exceptional circumstances up to 8 weeks is allowed; in the exceptional cases discussion with HQ is strongly recommended.

Histologically proven newly diagnosed atypical grade WHO grade II meningioma (≥ 4 mitosis per high-power field [HPF] or the presence of at least 3 of the latter 4 variables: cellularity, architectural sheeting (i.e. patternless pattern), macronuclei and small cell formation) (see section 3.1 below for definition)

OR

Histologically proven newly diagnosed malignant WHO grade-III meningioma (see section 3.1 below for definition) (as assessed by the local pathologist)

AND all of:  Complete or subtotal resection level reviewed by the surgeon after verification with a postoperative MRI and according to Simpson guidelines (see section 3.2 below for definition). The patients will be stratified according to the resection status: complete excision (Simpson’s stages 1-3) versus incomplete excision (Simpson’s stages 4-5)  Age between 18 years and 70 years  WHO performance status 0-2  All locations except optic nerve sheets tumors  No neurofibromatosis type II patients (NF-2)  No previous radiotherapy to the brain or meninges interfering with the protocol treatment plan  No clinical evidence of second malignancies, except a history of cervix carcinoma in situ and basocellular carcinoma  Women of reproductive potential must use effective contraception for the whole duration of the treatment and must not be pregnant or lactating.  Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial EORTC 22042-26042 Postop HD-RT for atypical and malignant meningioma Version 3.0 24 / 71 November 11, 2010  Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations. Patients can be registered in this trial only once.

CZS/Nelfinavir glioblastoma.doc

Inclusion criteria Histologically confirmed glioblastoma multiforme at primary diagnosis Tumours which do enhance on pre-operative imaging Age >=18-70 years WHO performance status 0-2, RTOG- RPA class III-IV. No recent (< 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction) Patient able to tolerate full course of radiotherapy No previous radiotherapy to the head and neck area. Prior neurosurgery within 6 weeks of treatment No previous irradiation of the brain. No previous chemotherapy No prior or concurrent medical condition which would make treatment difficult to complete. Medication with steroids is allowed. No use of terfenadine, astemizol, cisapride, sildenafil, lovastatin or simvastatin and other concurrent medication that is metabolized by the CYP3A4 isoenzyme and cannot be replaced with other equivalent medications for the period of the study: antiarrhythmics (amiodarone, quinidine), neuroleptics (pimozide), sedative/hypnotic agents (e.g. midazolam, triazolam), ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), HMG-CoA reductase inhibitors (e.g. lovastatin, simvastatin), rifampin, rifabutin, felodipine, nifedipine, and sildenafil or St. John's wort. Adequate haematological, renal and hepatic function No uncontrolled infectious disease, absence of known HIV infection, chronic hepatitis B or hepatitis C infection Absence of any medical condition, which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction) All patients of reproductive potential (male and female) must use effective contraception for the whole duration of the treatment and until 6 months thereafter. Females must not be pregnant or lactating Willing and able to comply with the study prescriptions Written informed consent before patient registration


Endometrium/PORTEC-3.doc

Inclusion Criteria:

Histologically confirmed endometrial carcinoma, with one of the following postoperative FIGO stages and grade: 1. stage IB grade 3 with documented LVSI 2. stage IC or IIA grade 3 3. Stage IIB 4. stage IIIA or IIIC (IIIA based on cytology alone only eligible if grade 3) 5. stage IB or IC, stage II or stage III with serous or clear cell histology WHO-performance status 0-2 WBC ≥ 3.0 x 109/L. Platelets ≥ 100 x 109/L. Bilirubin ≤ 1.5 x UNL ASAT/ALAT ≤ 2.5 x UNL Written informed consent

Exclusion Criteria:

Previous malignancy (except for basal cell carcinoma of the skin) < 10 yrs Previous pelvic radiotherapy Hormonal therapy or chemotherapy for this tumor Macroscopic stage IIB for which Wertheim type hysterectomy Prior diagnosis of Crohn’s disease or ulcerative colitis Residual macroscopic tumor after surgery Creatinine clearance ≤ 60 ml/min (Cockroft) or ≤ 50 ml/min (EDTA clearance, or measured creatinine clearance) Impaired cardiac function, prohibiting the infusion of large amounts of fluid during cisplatin therapy Peripheral Neuropathy > grade 2


Hoofdhals/HX4 hoofdhals.doc

5.4 Inclusion criteria - Histological or cytological confirmed HNSSC of the oral cavity, oropharynx, hypopharynx, larynx, T2-T3-T4, any N, M0 - Tumor (or lymph node) diameter ≥ 2,5 cm - WHO performance status 0 to 2 - Scheduled for primary curative (concurrent chemo-) radiotherapy - No previous surgery to the head and neck - No previous radiation to the head and neck - Adequate renal function (calculated creatinine clearance at least 60 ml/min). - The patient is willing and capable to comply with study procedures - 18 years or older - No recent (< 3 months) myocardial infarction - No uncontrolled infectious disease - Not pregnant or breast feeding and willing to take adequate contraceptive measures during the study - Have given written informed consent before patient registration


Lever/SAKK7707.doc

6.1 Inclusion criteria 6.1.1 Patient must give informed consent before registration. 6.1.2 Histologically, cytologically or radiologically confirmed diagnosis of HCC (see Appendix 21.1 for radiological criteria). 6.1.3 Stage cT2-4, cN0-1, M0 or unresectable cT1, cN0-1, M0 (see Appendix 21.2 for TNM staging). Note: In phase I of the trial, M1 is allowed if at least 90% of the tumor load (volume) is in the liver. 6.1.4 Cirrhosis Child-Pugh class A or B (Child-Pugh score of ≤ 9, see Appendix 21.3). 6.1.5 Measurable disease (at least one liver lesion that can be measured in at least one dimension as ≥ 10 mm in multislice CT/MRI). 6.1.6 Volumetry of liver tumor and residual liver tissue: residual liver volume (= total liver volume – GTV) has to be ≥ 800 ml and ≥ 40% of total liver volume. 6.1.7 WHO performance status 0-2 (see Appendix 21.4). 6.1.8 Adequate hematological values: hemoglobin ≥ 100 g/L, neutrophils ≥ 1.2 x 109/L, platelets ≥ 50 x 109/L. 6.1.9 Adequate hepatic function: ALT and AST ≤ 7 x ULN, AP ≤ 10 x ULN, bilirubin ≤ 50 μmol/L. 6.1.10 Adequate coagulation parameter: INR ≤ 2. 6.1.11 Adequate renal function: calculated creatinine clearance ≥ 50 mL/min (formula Cockcroft- Gault, see Appendix 21.5), functional left kidney (scintigraphy mandatory for phase I, phase II only if indicated). 6.1.12 Age ≥ 18 years. 6.1.13 Ability to tolerate proton-pump inhibitors (PPI) or H2 antagonists during RT to reduce risk of gastrointestinal bleeding in region of RT. 6.1.14 Women must not be pregnant, must use effective contraception and must not become pregnant during treatment period if sexually active. A negative pregnancy test is mandatory for all women < 50 years (unless considered unnecessary by the investigator). Men agree not to father a child during participation in the trial or during the 4 months thereafter. 6.1.15 Patient compliance and geographic proximity allow proper staging and follow-up. 6.1.16 Applicable for phase I only: adequate pancreatic function: lipase ≤ 2 x ULN.

6.2 Exclusion criteria 6.2.1 Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer. 6.2.2 Previous RT to the abdomen (not pelvis) or caudal chest (below D5) Note: Patients with portal vein embolization/ligation or pre-RT TACE are eligible. 6.2.3 TACE, RFA or RT within 8 weeks before registration (unless documented progressive Radiotherapy in HCC SAKK 77/07 Final version, 29 August 2008 Page 15 of 55 disease after treatment). 6.2.4 Concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 21 days prior to registration. 6.2.5 Operable disease (with curative intent) or planned liver transplantation. 6.2.6 Nutritional intake < 1500 calories per day (corrected). 6.2.7 Weight loss ≥ 15 % within 3 months before registration. 6.2.8 Presence of clinical ascites. 6.2.9 Presence of encephalopathy (medically not controlled). 6.2.10 Recent myocardial infarction (i.e. within 6 months prior to registration). 6.2.11 Esophageal varices ≥ grade 3 or esophageal varices with red signs or bleeding of esophageal varices within the last 3 months. 6.2.12 Symptoms of colitis, enteritis, esophagitis, fistula, gastritis, ileus, necrosis, perforation, stricture or ulcer. 6.2.13 Severe anorexia, constipation, dehydration, diarrhea or vomiting. 6.2.14 Any serious underlying medical condition (at the judgment of the investigator), which could impair the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes). Note: Patients with portal vein thrombosis are eligible. 6.2.15 Concomitant treatment with steroids or NSAIDs during RT (PPIs allowed). 6.2.16 Psychiatric disorder precluding understanding of information on trial related topics or giving informed consent.


Longen (NSCLC)/1. PET boost

Eligibility criteria

  • Patients > 18 years with any subtype of pathologically proven (biopsy or cytology), non-small cell lung cancer. The diagnosis may be established from biopsy or cytology obtained from the primary tumor and/ or from metastatic lymph nodes.
  • Minimal diameter of the primary tumor 4 cm, this to allow for boosting of subvolumes.
  • UICC Stage T2-4, N0-3, M0 disease (TNM definition see appendix 2).
  • Only stage IB-II patients who are not candidates for surgery are study candidates.
  • Measurable disease at registration.
  • ECOG-performance status ≤ 2 (see appendix 6)
  • Lung function: FEV1 and DLCO at least 40 % of the age-adjusted normal value
  • Willing and able to give a written informed consent.
  • Patients with locoregional recurrent lung tumor following surgery or a second primary cancer (at least 3 years after treatment) are eligible, unless a pneumonectomy was performed.
  • SUVmax in the pre-treatment FDG-PET scan ≥ 5 for the primary tumor.
  • Adequate organ function, including the following:
    • Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1.5 x 109/L, platelets ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL.
    • Hepatic: bilirubin ≤ 1.5 times the upper limit of normal (× ULN); alkaline phosphatase (AP), aspartate aminotransferase (ASAT), and alanine aminotransferase (ALAT) ≤ 3.0 × ULN .
    • Renal: calculated creatinine clearance (CrCl) ≥ 45 ml/min based on the original weight based Cockcroft and Gault formula.
  • For women: Must be surgically sterile, postmenopausal, or compliant with a highly reliable contraceptive method (failure rate <1%) during and for 6 months after the treatment period or must have a negative serum or urine pregnancy test within 7 days before study enrollment, and must not be breast-feeding.
  • For men: Must during chemotherapy take adequate contraceptive measures.

Ineligiblity criteria

Prior radiotherapy to the thorax. Clinical superior vena cava syndrome, malignant pleural effusion or malignant pericardial effusion. Tumor growth in large blood vessels on spiral CT scan (encasement is eligible). T4 because of multiple nodules in the same or ipsilateral lobe(s). Post-obstructive atelectasis or infiltration that cannot be distinguished from tumor on a CT-PET scan. Patients with a diagnosis of other cancer within the last 3-years (except in situ carcinoma’s and / or non-melanoma skin cancer). Pregnant women, lactating women. For patients recieving pemetrexed: unable/unwilling to take folic acid, vitamin B12, and dexamethasone unable to interrupt NSAIDs yellow fever vaccination within 30 days previous to study entry

Pretreatment studies

Complete medical history, and physical examination including weight, height, ECOGperformance status. heart rate, blood pressure. Blood analysis including: Hb, Ht, Leukocytes, platelets Na, K, Ca, Phosphate, Albumin, Alkaline phosphatase, gamma GT, ASAT, ALAT, LDH, creatinine, albumine PA and lateral chest X-ray. Bronchoscopy with histologic and/or cytologic specimens. When the diagnosis was established on the basis of histology or cytology obtained from lymph nodes, these patients are also eligible for the trial. CT-scan with contrast of the chest and upper abdomen to include liver and adrenal glands. A CT scan of this area obtained during PET-CT is eligible. Whole body FDG PET-CT scan < 4 weeks before radiotherapy begins (may be combined with 5.), according to the NEDPAS protocol (appendix 11) Brain imaging: CT scan with intravenous contrast or MRI scan. Electrocardiogram (ECG). Cough, dysphagia and dyspnea scoring according to the CTCAE version 3.0 criteria, (see appendix 5). Pulmonary function tests (TLC, VC, RV, FEV1 and TLCO) Patient questionnaires: QoL EORTC C30 and LC 13 Euroqol5D

Longen (NSCLC)/2. Nitroglycerine.doc

Inclusion criteria Non-small cell lung cancer stage IB-IV amenable for radiotherapy with curative intent. Patients not included in PET-boost trial WHO performance status 0-2 Willing and able to comply with the study prescriptions 18 years or older Ability to give and having given written informed consent before patient registration No recent (< 3 months) severe cardiac disease (NYHA class >1) (congestive heart failure, infarction) No radiotherapy in 4 weeks prior to this study No treatment with investigational drugs in 4 weeks prior to or during this study. No known allergy to nitroglycerin or nitroglycerin patch. No use of Levitra, Viagra or Cialis at the time of application of the nitroglycerin patch. No conditions necessitating the use of ergot alkaloids, alpha blockers (eg tamsulosine), beta-blockers or calcium channel blockers on the day of nitroglycerin patch application. No other active malignancy. No major surgery (excluding diagnostic procedures like e.g. mediastinoscopy) in previous 4 weeks. Adequate renal function: calculated creatinine clearance at least 60 ml/min.


Longen (NSCLC)/3a. NVALT-11.doc

4. Patient selection

4.1 Eligibility for registration

UICC stage III A or IIIB (without malignant pleural or pericardial effusion) nonsmall cell lung cancer (histology or cytology) Whole body FDG-PET-scan before the start of therapy available: No distant metastases CT or MRI of the brain before the start of therapy available: No brain metastases No other malignancy in the preceding 2 years, except non-melanoma skin cancer or any carcinoma in situ. No prior cranial irradiation Patient should be suitable for radical treatment with Platinum-based chemotherapy and is planned to receive radical loco-regional therapy: concurrent or sequential chemotherapy (Platinum-based) and radiotherapy with or without surgery (Radiotherapy dose without surgery at least a biological equivalent of 60 Gy (20)) Patients must sign a study-specific informed consent at the time of registration. At the same time, thus before randomization, the baseline forms (CTCAE3.0, QLQ-C30 and EuroQol 5D) should be filled out. Pregnant women are ineligible as treatment involves unforeseen risks to the participant and to the embryo or fetus; patients with childbearing potential must practice appropriate contraception

4.2 Conditions for Patient eligibility at randomization

Patient has been registered in the study and has completed appropriate radical treatment, no more than 6 weeks before. Registration is thus allowed either before or after radical therapy. The patient is ready to receive PCI within 1 week of randomization (if randomized to PCI arm) There is no clinical evidence of progressive disease after chemo-radiation (no imaging is requested) No evidence of extracranial distant metastatic disease Signed informed consent for randomization

Patients who were registered, but not randomized, will not be followed-up in this study


Longen (NSCLC)/3b. PCI cognitie.doc

4.1 Population (base) Patients will be recruited from 5 hospitals participating in the phase III trial: Prophylactic Cranial Irradiation (PCI) versus observation in radically treated patients with stage III non-small lung cancer: a phase III randomized study ((NVALT 11/DLCRG-02). Eligibility criteria for participating in this trial include: UICC stage III A or III B (without malignant pleural or pericardial effusion) non-small cell lung cancer Whole body PDG-PET scan before the start of therapy available: no distant metastasis. CT or preferably MRI of the brain before the start of radical therapy available; no brain metastasis. Platinum-based chemotherapy is mandatory. Radical local therapy: concurrent or sequential chemotherapy and radiotherapy with or without surgery. Radiotherapy dose without surgery to at least biological equivalent of 60 Gy. No prior cranial irradiation.

4.2 Additional Inclusion criteria for the sub-study sufficient proficiency in Dutch language MRI (and not CT scan) pre-PCI 4.3 Additional Exclusion criteria none


Longen (NSCLC)/Flowchart PCI cognitie I.doc

Longen (NSCLC)/schema_PCI cognitie.xls