TRANS TASMAN RADIATION ONCOLOGY GROUP INC · 2015-07-22 · trans tasman radiation oncology group limited acn 132 672 292 in collaboration with australasian lung cancer trials group

TRANS TASMAN RADIATION

ONCOLOGY GROUP LIMITED

ACN 132 672 292

In collaboration with

Australasian Lung cancer Trials Group

TROG 11.03

A RANDOMISED PHASE III TRIAL OF HIGH DOSE PALLIATIVE

RADIOTHERAPY (HDPRT) VERSUS CONCURRENT

CHEMOTHERAPY + HDPRT (C-HDPRT) IN PATIENTS WITH

GOOD PERFORMANCE STATUS, LOCALLY ADVANCED OR

METASTATIC NSCLC WITH SYMPTOMS PREDOMINANTLY DUE

TO INTRATHORACIC DISEASE WHO ARE NOT SUITABLE FOR

RADICAL CHEMO-RADIOTHERAPY (P_LUNG GP)

Final Protocol: 5 April 2012

Amendment 1: 25 May 2012

Amendment 2: 07 September 2012

Amendment 3: 05 August 2013

Amendment 4: 13 October 2014

Trial Chairperson: Assoc Prof Margot Lehman Radiation Oncology Princess Alexandra Hospital T: +61 (0) 7 3176 2111 F: +61 (0) 7 3176 2252 E: [email protected]

Trial Co Chairperson: Assoc. Prof Michael Michael Medical Oncology Peter MacCallum Cancer Institute, T: +61 (0) 3 9656 1111 F: +61 (0) 3 9565 1424 E: [email protected]

Trial Coordinator: Cassie Freriechs Cancer Trials Unit Princess Alexandra Hospital T: +61 7 3176 8292 F: +61 7 3176 1929 E:[email protected]

mailto:[email protected]


TROG 11.03 P_LUNG GP Final Version 5 April 2012 Amendment 4: 13 October 2014 Page 2 of 127

CONFIDENTIAL

PROTOCOL AUTHORISATION PAGE

Final Protocol: 5 April 2012

Amendment 4: 13 October 2014

TROG 11.03 A RANDOMISED PHASE III TRIAL OF HIGH DOSE PALLIATIVE

RADIOTHERAPY (HDPRT) VERSUS CONCURRENT CHEMOTHERAPY + HDPRT (C-

HDPRT) IN PATIENTS WITH GOOD PERFORMANCE STATUS, LOCALLY ADVANCED OR

METASTATIC NSCLC WITH SYMPTOMS PREDOMINANTLY DUE TO INTRATHORACIC

DISEASE WHO ARE NOT SUITABLE FOR RADICAL CHEMO-RADIOTHERAPY

(“P_LUNG GP)”

Trial Chairpersons: Assoc Prof Margot Lehman (Radiation Oncology)

Princess Alexandra Hospital Ipswich Road Woolloongabba, Queensland, 4102 Assoc. Prof Michael Michael (Medical Oncology) Peter MacCallum Cancer Institute,

St Andrews Place, East Melbourne 3002

Signature Date Signature Date

Sponsor: TROG (Trans Tasman Radiation Oncology Group) Ltd Central Operations Office Calvary Mater Newcastle Locked Bag 7 HRMC NSW 2310

TROG Representative: Joan Torony TROG Research Manager

Signature Date

Note: Original and signed document held at TROG Central Operations Office


FOREWORD This document is intended to describe a Trans Tasman Radiation Oncology Group (TROG) trial and to provide information about procedures for screening, enrolling and treating trial participants. It is not intended that the Protocol be used as a guide for the treatment of patients who are not enrolled on this trial. TROG will not accept any data for analysis unless each Trial Site has Human Research Ethics Committee (HREC) approval for patient enrolment and participation in this trial. Amendments to the document may be necessary; when approved by TROG, these will be circulated by the Trial Coordinating Centre, on behalf of TROG, to Trial Sites participating in the Trial. The Protocol and all other trial related documentation including the Participant Information Sheet and Consent Form and Case Report Forms must be written in English and under no circumstances be translated into another language without prior written approval from TROG.

Trial Management Committee

Trial Chairpersons

Assoc Prof Margot Lehman (Radiation Oncology) Assoc. Prof Michael Michael (Medical Oncology)

Radiation Oncology

NSW: Assoc Prof Shalini Vinod, Dr Jane Ludbrook, Dr Patrick Dwyer VIC: Prof David Ball

Medical Oncology Assoc. Prof Michael Michael (Medical Oncology)

Radiation Therapy Ms Michelle Mauro, Princess Alexandra Hospital Physics Ms Catherine Jones, Princess Alexandra Hospital Translational Research Dr Michelle Hill Quality of Life Professor Madeleine King Pathology Associate Professor Glenn Francis Statistician Associate Professor Richard Fisher Central Trial Coordinator Ms Cassie Freriechs Consumer Mr Ian Stubbin


TABLE OF CONTENTS

1.0 SYNOPSIS ................................................................................................................ 8

1.1 Objectives .................................................................................................................. 8

1.2 Inclusion Criteria ........................................................................................................ 8

1.3 Exclusion Criteria ...................................................................................................... 9

2.0 BACKGROUND INFORMATION ............................................................................ 11

2.1 Description of disease ............................................................................................. 11

2.2 Current Standard of Care ........................................................................................ 11

2.3 Treatment Approaches ............................................................................................ 11

2.3.1 Palliative Radiotherapy ................................................................................ 12

2.3.2 Palliative Chemotherapy .............................................................................. 13

2.4 Previous Studies of Palliative Radiotherapy and Concurrent Chemotherapy ....... 14

2.4.1 Phase I trials ................................................................................................ 14

2.4.2 Phase II Trial ................................................................................................ 15

2.4.3 Rationale for Phase III Trial Design .............................................................. 15

3.0 TRIAL OBJECTIVES AND ENDPOINTS ................................................................ 18

3.1 Hypothesis ............................................................................................................... 18

3.2 Objectives ................................................................................................................ 18

3.2.1 Primary Objective ......................................................................................... 18

3.2.2 Secondary Objectives .................................................................................. 18

3.2.3 Exploratory/Tertiary Objectives .................................................................... 18

3.3 Endpoints ................................................................................................................ 19

3.3.1 Primary Endpoints ........................................................................................ 19

3.3.2 Secondary Endpoints ................................................................................... 19

4.0 TRIAL DESIGN ....................................................................................................... 20

4.1 Trial design .............................................................................................................. 20

4.2 Total Participant Accrual .......................................................................................... 20

5.0 PARTICIPANT SELECTION ................................................................................... 20

5.1 Inclusion Criteria ...................................................................................................... 20

5.2 Exclusion Criteria .................................................................................................... 21

6.0 REGISTRATION AND RANDOMISATION .............................................................. 21

6.1 Screening and Registration ..................................................................................... 21

6.2 Randomisation ........................................................................................................ 21

6.3 Central Trial Coordinator Contact Details................................................................. 22

7.0 TREATMENT REGIMEN ......................................................................................... 22

7.1 Radiotherapy ........................................................................................................... 22

7.1.1 Treatment aim and rationale ........................................................................ 22

7.1.2 Treatment Schedule ..................................................................................... 22


7.1.3 Planning Simulation ..................................................................................... 23

7.1.4 Target Volume definitions and dose constraints ........................................... 23

7.1.5 Normal tissue contouring and dose constraints ............................................ 24

7.1.6 Dose prescription and fractionation: ............................................................. 24

7.1.8 Treatment Verification and Delivery ............................................................. 26

7.1.9 QA Reporting ............................................................................................... 26

7.1.10 Treatment Equipment Specifications/Physical Factors ................................. 28

7.2 Chemotherapy ......................................................................................................... 29

7.2.1 Treatment Schedule ..................................................................................... 29

7.2.2 Chemotherapy Administration and Dosage .................................................. 29

7.2.3 Dose definition and number of cycles........................................................... 30

7.2.4 Technique of drug administration and premedication ................................... 31

7.2.5 Sequence of timing of drug administration relative to radiotherapy: (Arm B) 31

7.2.6 Duration of treatment: Arm B ....................................................................... 32

7.2.7 Toxicity criteria expected effects and their timing: Arm B ............................. 32

7.2.8 Dose modification: Arm B ............................................................................. 32

7.2.9 Calculation of body surface area ....................................................................... 34

7.2.10 Non-permitted medications/treatments ......................................................... 34

7.2.11 Drug Supply ................................................................................................. 34

7.2.12 Investigator’s Brochure ................................................................................ 34

7.2.13 Monitoring Toxicity and Modifications ........................................................... 34

8.0 TRIAL PARTICIPANT ASSESSMENTS ................................................................. 35

8.1 Pre-Registration Assessments ................................................................................. 35

8.2 Pre-Treatment Assessments ................................................................................... 35

8.3 Assessments During Treatment ............................................................................... 36

8.4 End of Treatment Assessments ............................................................................... 36

8.5 Follow-up Assessments ........................................................................................... 37

8.6 Disease Progression Assessments: ......................................................................... 37

8.7 Completion of Quality of Life (QoL) Questionnaires ................................................. 38

9.0 PATIENT PREFERENCES STUDY ..................................................................... 40

9.1 Objectives ........................................................................................................... 40

9.2 Research Plan ..................................................................................................... 40

10.0 BIOLOGICAL SUBSTUDY ................................................................................. 41

11.0 ASSESSMENT OF EFFICACY ........................................................................... 42

11.1 Endpoint Definitions ............................................................................................ 42

11.1.1 Primary Endpoints ........................................................................................ 42

11.1.2 Secondary Endpoints ................................................................................... 42

11.2 Assessment Tools ............................................................................................... 43

11.2.1 Quality of Life (QOL) Questionnaire ............................................................. 43


12.0 ADVERSE EVENT SCORING and REPORTING ............................................... 44

12.1 Definitions ........................................................................................................... 44

12.1.1 Adverse Event (AE) ..................................................................................... 44

12.1.3 Serious Adverse Event (SAE) ...................................................................... 45

12.1.4 Attribution of Cause of an Adverse Event ..................................................... 46

12.2 Reporting ............................................................................................................ 46

12.2.1 Adverse Event Reporting ............................................................................ 46

12.2.2 Serious Adverse Event Reporting ................................................................ 47

12.2.3 Other situations requiring expedited reporting .............................................. 48

12.3 New Zealand reporting requirements .................................................................. 49

13.0 TREATMENT DISCONTINUATION, WITHDRAWAL/TRANSFER ..................... 49

13.1 Protocol Treatment Discontinuation .................................................................... 49

13.2 Withdrawal from Trial .......................................................................................... 49

13.3 Patient Transfers ................................................................................................. 50

14.0 STATISTICAL CONSIDERATIONS .................................................................... 50

14.1 Trial Design ......................................................................................................... 50

14.2 Treatment Assignment ........................................................................................ 50

14.3 Statistical Methods .............................................................................................. 50

14.4 Sample Size Calculation and Expected Duration ................................................ 51

14.5 Analysis Plan ...................................................................................................... 52

14.6 Early Termination Criteria .................................................................................... 53

15.0 DATA MANAGEMENT AND QUALITY ASSURANCE ....................................... 53

15.1 Trial Site Data Management ................................................................................ 53

15.2 Source Documents.............................................................................................. 54

15.3 Quality Assurance Reviews ................................................................................. 54

15.3.1 Regulatory Reviews ..................................................................................... 54

15.3.2 Eligibility Reviews ........................................................................................ 54

15.3.3 QoL Questionnaire compliance reviews ....................................................... 54

15.3.4 Radiotherapy Treatment Delivery ................................................................ 54

15.3.5 Chemotherapy Reviews ............................................................................... 54

15.4 Site Visits and Monitoring .................................................................................... 55

15.5 Data Monitoring Committee ................................................................................. 55

16.0 ETHICAL CONSIDERATIONS ........................................................................... 55

16.1 Ethical Principles and Regulatory Compliance .................................................... 55

16.2 Adherence to Protocol ......................................................................................... 55

16.3 Informed Consent ............................................................................................... 55

16.4 Confidentiality ..................................................................................................... 56

17.0 INSURANCE AND COMPENSATION ................................................................ 56

18.0 PUBLICATION AND PRESENTATION POLICY ................................................ 56


18.1 Reporting of Results ............................................................................................ 56

18.2 Trial Registry ....................................................................................................... 56

19.0 REFERENCES ................................................................................................... 57

Appendix 1 Staging ..................................................................................................... 61

Appendix 2 ECOG Performance Status Criteria ........................................................ 63

Appendix 3 Cockcroft-Gault Formula for Calculating Creatinine Clearance .......... 64

Appendix 4 Physician rated Spitzer Index ................................................................. 65

Appendix 5 Karnofsky Performance Scale Index ...................................................... 67

Appendix 6 Schedule of Assessments ...................................................................... 68

Appendix 7 CTCAE (Common Terminology Criteria for Adverse Events, V3.0) ..... 70

Appendix 8 Quality of Life Questionnaires ................................................................ 71

Appendix 9 Recist Response Criteria ........................................................................ 74

Appendix 10 Radiotherapy ......................................................................................... 75

Appendix 11 Participant Information Sheet and Consent Form .............................. 77

Appendix 12 Collection of blood and tissue specimens .......................................... 93

Appendix 13 Participant Information Sheet and Consent Form – Patient Preferences Survey ............................................................................................... 99

Appendix 14 Lung Cancer – Treatment Preferences Study ................................... 105


1.0 SYNOPSIS

1.1 Objectives

The primary objective of this trial is to compare, in this group of patients, high dose palliative radiotherapy (HDPRT) versus concurrent chemotherapy and HDPRT (C-HDPRT), with respect to the relief of dyspnoea, cough, haemoptysis and chest pain as assessed by change in total symptom burden from baseline to six weeks after the completion of treatment, and the response for each component symptom separately (dyspnoea, cough, haemoptysis, chest pain) Secondary Objectives of the trial include the comparison of the two regimens in terms of dysphagia during treatment, thoracic symptom response rate, duration of thoracic symptom response, Quality of Life (QOL), toxicity, progression-free survival, and overall survival

1.2 Inclusion Criteria

Aged 18 years or older

ECOG PS 0-1,

Histological or cytological proven stage III or IV NSCLC of any subtype: Adenocarcinoma, Squamous Cell Carcinoma (SCC), NSCLC Not Otherwise Specified (NOS) or Other (including Large Cell Undifferentiated).

Symptoms due to intrathoracic disease (at least one of cough, dyspnoea, haemoptysis, chest pain),

Patients with Stage III NSCLC not suitable for radical chemo-radiotherapy (due to concurrent medical illness, weight loss > 10%, or tumour volume too large for radical radiation fields (e.g. dose constraints for organs at risk cannot be met using radical radiation fields or at the discretion of the investigator)

Patients with metastatic disease of any site or extent who have symptoms predominantly due to intrathoracic disease.

Planned for HDPRT to achieve local control and symptom relief

Adequate organ function;

o Bone marrow: Haemoglobin (Hb) ≥ 100g/l, Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Platelet count ≥ 100 x 109/L

o Hepatic: Serum bilirubin ≤ 1.0 x upper limit of normal (ULN), AST/ALT ≤ 2.0 x ULN, ALP ≤ 2.5 x ULN.

o Renal: Creatinine Clearance ≥ 55 ml/min (Cockcroft-Gault formula – see appendix 3)

No prior therapy for NSCLC

Able to commence Radiotherapy no later than 6 weeks, but preferably within 4 weeks from the time of participant randomisation. It is preferred that RT be commenced on a Monday or Tuesday.

Has provided written informed consent to participate in this trial

Participants capable of childbearing are using adequate contraception

Available for follow-up for a minimum of 3 months.


1.3 Exclusion Criteria

Receiving treatment with another investigational agent

History of any other cancer (except non-melanomatous skin cancer or carcinoma in situ of the cervix) unless in complete remission and off all therapy for that cancer for at least 3 years.

Women who are pregnant or lactating

Previous radiotherapy to the area to be treated, at any time

Significant medical conditions which in the opinion of the investigator would compromise the planned delivery of the chemotherapy and radiotherapy or which may be potentially exacerbated by these modalities

1.4 Registration/Randomisation contact details Please refer to the TROG11.03 Data Management Procedures document or contact the Central Trial Coordinator for registration/randomisation procedures. Cassie Freriechs Clinical Trials Unit Division of Cancer Services Princess Alexandra Hospital Ipswich Road, Woolloongabba Qld 4102 T: +61 (0)7 3176 8292 F: +61 (0)7 3176 1929 - trial correspondence only, NOT CRFs E: [email protected] TROG Teleform Fax: (0)2 4014 3618 – fax submission of all CRFs Trial Coordinating Centre Office hours: Monday to Friday 08.30am to 5.00pm Australian EST

1.5 Schematic Diagram

Ran

do

mis

ati

on

ELIGIBILITY (includes)

Stage III-IV NSCLC

Planned high-dose,

palliative RT

At least one of the

symptoms:

dyspnoea

cough

haemoptysis

chest pain

Refer to section 1.2 and 1.3 of

synopsis for complete criteria

STRATIFICATION (minimisation)

Stage (III, IV)

NSCLC

Histology

(AdenoCa, SCC,

NSCLC NOS,

other)

Dyspnoea,

cough,

haempotysis,

chest pain (N/Y)

Treating

institution

R A N D O M I S A T IO

N

ARM B: C-HDPRT

40GY in 20 fx (2Gy/fx, 4-

5fx/week) +

Cisplatin 20mg/m2 IV, d

1,8,15,22 +

Vinorelbine 25mg/m2 IV d

1,8,22

ARM A: HDPRT

RT 36Gy/12fx (3Gy/fx, 4-

5 fx/week

I NFORMED

CONSENT



1.6 Patient Assessments

1.7 Description of Radiation Therapy Treatment Arm A (control arm): High dose palliative Radiation Therapy alone (HDPRT). 36Gy/12f (3Gy/f, 4-5f/week) Arm B (investigational arm): Chemotherapy + HDPRT (C-HDPRT) 40Gy/20f (2Gy/f, 4-5f/week) 1.8 Description of Chemotherapy Treatment Arm A (control arm): No chemotherapy Arm B (investigational arm): IV Cisplatin 20mg/m2 days 1, 8, 15, 22 + IV Vinorelbine 25mg/m2 days 1, 8, 22 1.9 Follow-up Schedule Patients will be followed up weekly during treatment and then at 2 and 6 weeks post treatment and then 3 monthly thereafter until disease progression. 1.10 Sample Size and Duration The number of participants that will be accrued for this trial is 130. It is anticipated it will take 41 months to complete accrual, with a further 14 months of follow-up.

1.11 Patient Preferences Sub-Study Patients who consent to participate in the TROG 11.03 PLUNG study will also be invited to participate in a Patient Preferences Study. This will require the patient to undergo an additional informed consent process and sign a consent form specific to the Patient Preferences Study (see section 9 of the TROG 11.03 PLUNG Protocol).


2.0 BACKGROUND INFORMATION

2.1 Description of disease

Lung cancer is the fifth most common cancer in Australia (accounting for 9.2% of all new cancer cases in 2004), and the leading cause of cancer deaths (responsible for 19.1% of all cancer deaths or 7399 deaths in 2005). (1) The majority of lung cancers are of the NSCLC histological type and most patients present with inoperable Stage III or IV disease. (2)

2.2 Current Standard of Care

Patients with inoperable NSCLC can be divided into three groups(3):

1. Patients with good PS and localised tumour who should be considered for radical treatment with the accepted standard of care being the concurrent administration of chemotherapy (CT) and radiotherapy (RT) to doses ≥60Gy. Phase III trials demonstrate a survival advantage, in this group of patients, when cisplatin-based chemotherapy is administered concurrently with RT versus RT alone (4-6) and when concurrent CT-RT is compared with the sequential administration of CT and RT. (7,8)

2. Patients with poor PS and advanced or metastatic tumour for whom simple,

established palliative measures are appropriate; and

3. An intermediate group of patients who have a good PS but locally advanced or limited metastatic disease for whom radical CT-RT (≥60Gy) is not feasible either due to tumour extent or patient factors. In these patients, the aim of therapy is to achieve symptom control and maintain Quality of Life (QOL). However, the optimal treatment regimen for this group is uncertain. This patient group represents the population to be studied in this trial.

2.3 Treatment Approaches

Clinical practice in Australia for patients who have a good PS and locally advanced or limited metastatic disease for whom radical treatment is not possible, varies from the delivery of HDPRT alone (RT doses <60Gy) to relieve intra-thoracic symptoms followed by immediate or delayed chemotherapy, to the delivery of palliative chemotherapy alone with RT withheld until the progression of local symptoms. The concurrent administration of the two modalities has been avoided until recently due to concerns regarding the toxicity of this approach in patients receiving essentially palliative therapy.


2.3.1 Palliative Radiotherapy

The results of randomised controlled trials (RCTs) comparing different palliative radiotherapy regimens in locally advanced NSCLC are presented in Table 1.

Study Patient

Cohort Treatment Regimen

Overall response rate

Palliation Median Survival (m)

Simpson(9)

(1985) 409 Stage T4/N3

40Gy/10f 30Gy/10f 40Gy/20f

40% 44% 42%

24.5% symptom free 47% decreased symptom intensity

6.2 6.4 6.9 (ns)

Teo(10)

(1988) 273 Stage3/4 45Gy/18f

31.2Gy/4f 53% 50%

71% 54%

4.6m (ns)

Abratt(11)

(1995) 84 Stage 3

35Gy/10f 45Gy/15f

56% 51%

68% 78%

8.5 8.5 (ns)

MRC(12)

(1996) 509 AnyStage M0

17Gy/2f 39Gy/13f

ND 45-89% 7 9 (sig)

Rees(13)

216 17Gy/2f 22.5Gy/5

64-97%

ND

Reinfuss(14)

(1999) 240 Stage 3 50Gy/25f

40Gy/10f 20Gy/5f

12 9 6 (sig)

Nestle(15)

(2000) 152 Stage3/4 60Gy/30f

32Gy/16f 66% Up to 33% 8.4

(ns)

Bezjak(16)

(2002) 230 Stage 3/4

20Gy/5f 10Gy/1f

` ND 6 4.2 (sig)

Sundstrom(17)

(2004) 421 Stage 3/4

17Gy/2f 42Gy/15f 50Gy/25f

ND 20-90% 8.2 7 6.8 (ns)

Erridge(18)

(2005) 148 30Gy/10f

10Gy/1f 7

5.2 (ns)

Kramer(19)

(2005) 369 30Gy/10f

16Gy/2f 57-86% 19.6% v

10.9% (sig) 1yr Survival

Senkus-Konefka

(20)

(2005)

100 20Gy/5f 16Gy/2f

8 5.3

(ns) = not significant (sig) = significant ND = not detected

Table 1: RCTs presenting different palliative RT doses in locally advanced NSCLC

These studies have demonstrated heterogeneity in the age and performance status of the patients recruited, the dose regimens employed and the way in which key outcomes were assessed and reported.


Two systematic reviews of these data have been undertaken. A Cochrane review (21) of 14 RCTs involving 3576 evaluable patients found that palliative thoracic radiotherapy achieves reasonable rates of symptom control. However, there was no difference in specific symptom control rates between lower dose and higher dose schedules. The authors also concluded that there was strong evidence, from one large RCT (12) and three smaller studies (14, 16, 19) for an increase in survival (5% at 1 year and 3% at 2 years) in patients with good PS who were given higher dose RT. A second systematic review performed a quantitative pooling of the results of 13 RCTs comparing different dose fractionation schedules of palliative thoracic RT in 3473 patients. (22) The authors confirmed the findings of the previous systematic review in terms of no difference in the palliation of specific symptoms but reported that, in comparison with lower dose schedules, higher dose schedules (≥35Gy10 biologically equivalent dose, BED) resulted in:

A greater likelihood of symptom improvement on the total symptom score (Table 2)

A longer duration of symptom relief

An improvement in 1 year survival (26.5% v 21.7%, p =0.002) and

A higher incidence of toxicity, predominantly oesophagitis.

Symptom Complete response Any response

High dose (≥35Gy BED)

Low dose (≤35GyBED)

High dose Low dose

Haemoptysis 73.7% 68.9% ns 81.2% 80.2% ns

Cough 27.9% 32.1% ns 48.2% 53.5% ns

Chest pain 57.5% 51.9% ns 63.8% 64.8% ns

Total symptom score 16.2% 10% ns 60.9% 55.5% sig

High dose ≥35GyBED Complete response = complete resolution of symptom

Table 2: Symptom Response for individual symptoms and total symptom score comparing high dose and low dose RT schedules. Both systematic reviews concluded that, given the possibility of an improvement in total symptom score and overall survival, higher dose palliative RT (HDPRT) regimens should be considered for selected patients with good PS and locally advanced disease. Short courses of palliative RT should be considered for poor PS patients. 2.3.2 Palliative Chemotherapy In advanced NSCLC, systemic chemotherapy improves survival and maintains QOL compared with best supportive care. In a meta-analysis of 16 trials involving 2714 patients, chemotherapy reduced the risk of death (hazard ratio = 0.77; 95% CI 0.71-0.83; p≤ 0.0001), resulting in an absolute improvement in 1year survival of 9% (from 20% to 29%). (23) The most recent American Society of Clinical Oncology (ASCO) Clinical Practice guideline for Stage IV NSCLC recommends a platinum-based two-drug regimen of cytotoxic drugs for first-line therapy in patients with good performance status (PS of 0 or 1). (24) Studies which prospectively evaluate intrathoracic tumour-related symptoms demonstrate an improvement from baseline scores with palliative chemotherapy. (25)

Typically, palliative chemotherapy is delivered before or after palliative RT to avoid the toxicity of concurrent administration in the non-curative setting. The utility of combined


chemotherapy and radical radiotherapy (≥ 60Gy) has been validated in the curative setting, as discussed above. Patients with good PS and locally advanced or limited metastatic NSCLC who are not suitable for radical therapy frequently experience morbidity or mortality due to the consequences of local disease progression (e.g. lung/lobar collapse, pneumonia, haemoptysis) and hence better local control, in addition to systemic control, is of great clinical need. The concept of concurrent chemotherapy and high dose palliative radiotherapy (C-HDPRT) is thus a reasonable approach in such patients, with the rationale being that the two modalities work in a synergistic or additive fashion to improve local control. C-HDPRT has not been assessed in the Phase III setting. There have been 2 local phase I trials and a Trans Tasman Radiation Oncology Group (TROG) randomised phase II trial of C-HDRT in this setting, as described below, which form the basis of this planned phase III trial of C-HDPRT versus HDPRT.

2.4 Previous Studies of Palliative Radiotherapy and Concurrent Chemotherapy 2.4.1 Phase I trials Two Australian Phase I trials have evaluated the role of C-HDPRT in patients with locally advanced NSCLC who required locoregional control but were not suitable for radical therapy. Each trial determined the maximum tolerated dose (MTD) of two different C-HDPRT regimens.

In the first trial, 24 patients with Stage IIIB/IV disease and ECOG PS 0-1 received HDPRT (40Gy/20 fractions over four weeks) with weekly cisplatin + vinorelbine (days 1, 8, 22) escalated in 6 planned dose levels. Four weeks post RT patients received two cycles of cisplatin 80mg/m2 day 1 + vinorelbine 25mg/m2 days 1, 8, 15. Dose limiting toxicities were defined in the combined modality phase. The highest administered dose was dose level 4 (vinorelbine 30mg/m2 + cisplatin 20mg/m2) with dose limiting toxicities of grade 4 neutropenia in 2 of 3 patients but no grade 3/ 4 radiation-induced oesophagitis. The overall radiological rate was 65% (n=23: 4% complete response [CR] and 61% partial response [PR]) and infield FDG-PET responses were seen in 89% (n=18). There was an improvement or stabilisation of symptoms as assessed by the Lung Cancer Symptom Scale, and in QOL. Dose level 3, vinorelbine 25mg/m2 + cisplatin 20mg/m2, was recommended for further assessment. (26)

In the second study, 18 patients with Stage IIIA/B NSCLC unsuitable for curative therapy received palliative radiotherapy (30Gy/15fractions over three weeks) with gemcitabine given weekly before and within 3 hours of fractions 1, 6 and 11. The gemcitabine dose commenced at 100mg/m2 and was increased at 50mg/m2 increments until the maximum tolerated dose (MTD) was reached at 150mg/m2. The major acute toxicity was oesophagitis with 2 of 6 patients experiencing grade 3 oesophagitis in the 200mg/m2 arm. The overall response rate was 88% with 44% achieving a CR. (27)


2.4.2 Phase II Trial The promising activity demonstrated by the two C-HDPRT regimens in the Phase I trials discussed above led to their direct comparison in a randomised Phase II trial (TROG 03.07 with CI-Michael and CI-Burmeister as co-investigators) (28) with the aim of determining the superior regimen based on efficacy, toxicity and feasibility. Patients were eligible if they had an ECOG PS of 0 or 1 and Stage I-IIIB NSCLC, but were not suitable for curative therapy (because of disease extent, >10% weight loss or concurrent medical illness) or Stage IV disease with a FDG-PET detected solitary metastasis. Patients were randomised to either Arm A: 40Gy/20f (5f/week) + vinorelbine 25mg/m2 days 1, 8, 22 + cisplatin 20mg/m2 weekly or Arm B: 30Gy/15f (5f/week) + gemcitabine 200mg flat dose days 1, 8, 15. The major endpoints were response rate (based on RECIST criteria, assessing maximum response up to 3 months post therapy), feasibility and toxicity. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and QOL. Analysis was carried out on an intention to treat basis. QOL was assessed in all patients using a lung cancer specific questionnaire, the FACT-L. Between January 2004 and October 2007, 84 patients were randomised of whom > 80% had Stage III or IV disease. The median OS in Arm A was 13.12 months versus 8.13 months in Arm B (P >0.05). The median PFS was 5.52 months in Arm A and 4.6 months in Arm B (P > 0.05). The overall response rate (CR+ PR) was 70% in Arm A versus 50% in Am B (P = 0.14) with 1 patient in each arm achieving a CR. There was no significant difference in the pattern of relapse between the arms. There was no difference in the QOL impact between the 2 arms. Patients in Arm A experienced slightly more grade 3 toxicities than patients in Arm B but these toxicities were not clinically significant. The clinically significant grade 3 toxicities of dysphagia, dyspnoea, cough, nausea and fatigue were all less than 10% in both arms (Wilcoxon rank-sum test p = 0.006).

2.4.3 Rationale for Phase III Trial Design

The RT regimen employed in the control arm (36Gy/12f, 4-5f/week) is derived from the Medical Research Council LU13 trial. (12) This study randomised 509 patients with PS 0-2, of which 75% had PS 0-1, to receive either 17Gy in 2 fractions or 39Gy in 13 fractions. One third of patients in the latter group received 36Gy in 12 fractions due to concerns about spinal cord dose. The study found equivalent symptom control but an improvement in median survival of 54 days favouring the higher dose arm. Currently, 36Gy in 12 fractions is a widely employed palliative radiotherapy regimen used in good PS patients with locally advanced disease not suitable for curative regimens. The decision to use the 40Gy/20f + vinorelbine + cisplatin regimen of the preceding Phase II trial as the investigational arm is based on the following reasons: (1) A platinum-based doublet is considered the standard chemotherapy regimen in the palliative setting (24) and would be considered to provide appropriate radio-sensitisation. (2) 40Gy/20f is a biologically equivalent RT dose to 36Gy/12f. Thus, the addition of chemotherapy to a ‘like’ regimen is being tested. Chemotherapy is not being added to 36Gy/12f directly as the toxicity and feasibility of this regimen has not been assessed in Phase I or II trials. (3) The greater response rate, PFS and OS achieved by 40Gy/20f + vinorelbine + cisplatin regimen without a clinically significant increase in toxicity or QOL impairment relative to the other investigational arm in the preceding TROG Phase II trial.


2.4.3.1 Rationale for Patient Preferences Sub-study: Assessing what degree of improvement in QOL is necessary to justify longer treatment duration The regimens in this trial differ in treatment duration (2½ weeks versus 4 weeks). We aim to explore how much improvement in QOL would be necessary to make the inconvenience of each extra day of treatment worthwhile. We will employ a discrete choice experiment (DCE) methodology. In a DCE, respondents exercise their preferences by making repeated trade-offs and choices across a series of hypothetical scenarios whose attributes change in a systematic way (according to an underlying experimental design). In this case, the attributes will be the common symptoms (cough, dyspnoea, haemoptysis and chest pain), the main side-effect (dysphagia), aspects reflecting the inconvenience of attending for radiotherapy, and the duration of radiotherapy. Realistic levels of these attributes will be combined in a systematic fashion to develop a series of hypothetical scenarios. Experimental design principles will be used to select the optimal sample of scenarios with the appropriate statistical properties to allow the most efficient quantification of the effect of the attributes on the probability of choosing one alternative over another. Principles of the design and analysis of DCEs have been well explored and described.(29-31) DCEs provide a very powerful means of collecting preference data because they allow the influence of multiple attributes to be considered simultaneously and independently in a statistically rigorous way.(32,33) Thus DCEs provide a feasible means of determining which attributes patients are willing to trade-off in return for gains in other attributes. The practical application of DCE methods in health care has been demonstrated in several studies.(30,32,34-36) 2.4.3.2 Rationale for Discovery of Prognostic Biomarkers: Changes in Protein Glycosylation and Circulating Exosomes Despite advances in the treatment of NSCLC, outcomes remain poor. For patients suitable for radical chemo-radiotherapy, median survival figures of 16.5 to 20.6 months and 5 year survival figures of 20% have been reported. (7,8) A median survival of 9 months and a 2 year survival figure of 12% has been reported for patients not suitable for radical therapy receiving HDPRT. (12) Treatment outcomes will only be improved by a greater understanding of lung cancer biology, specifically an awareness of molecular predictive and prognostic markers. The discovery of predictive markers of chemotherapy and radiotherapy sensitivity may allow for the development of individually tailored treatment regimens which maximise efficacy and minimise toxicity. Several biological markers associated with chemo-sensitivity in NSCLC have been identified. (37-44) In contrast, less is known about the biomarkers involved in radiosensitivity or chemo-radiotherapy sensitivity in patients with locally advanced NSCLC. Changes in the type of protein glycosylation occur during tumour development and progression, leading to changes in cell adhesion, migration and the tumour microenvironment (45). Specifically, changes in cell surface glycosylation have been detected in lung cancer and metastases (46). Furthermore, expression of GalNAc-T3, and enzyme required for O-glycosylation, correlates with lung cancer prognosis and recurrence (47, 48). These results suggest that glycosylation changes are significant during lung cancer development and progression, and are potential prognostic biomarkers. Since glycosylated proteins are often secreted or shed from the cell surface, profiling the serum glycoproteome has been a recent focus in biomarker discovery, including several studies on lung cancer (49-54). However, these studies examined limited glyco-forms because existing glycoproteomics techniques were time-consuming and labour-intensive. Recognising the need for a high throughput screen for differential protein glycosylation, a novel lectin


magnetic bead array-coupled mass spectrometry workflow has been developed which will allow one-step isolation of glyco-forms from sera and the identification of a panel of glycoproteins that have altered glycan structures between cohorts (55). Following the technological development we now aim to screen patient serum samples to derive a panel of putative glycoprotein biomarkers for validation. Exosomes are small (50-100 nm) vesicles secreted from many cell types, including tumour cells, and are comprised of a specific subset of cellular components, including proteins, (membrane) lipids, and RNA. For lung cancer, a recent study reported a significantly increase exosomal protein and small RNA content correlating with lung cancer diagnosis. (56) Importantly, the profile of 12 microRNA (miRNA) species examined was highly similar in exosome and tumour of the same patient, supporting the hypothesis that exosomes are a good source of biomarkers. (56)

2.4.3.3 Collection and Banking of Biological Specimens: Access to tissue for future research This randomised study presents an excellent opportunity for the collection of tumour tissue and blood specimens that can subsequently be assayed for various biological markers. Correlating treatment outcomes with these findings may contribute to our knowledge of the factors which predict for sensitivity or resistance to radiotherapy and chemo-radiotherapy and for treatment-related toxicity. In consenting patients, a blood sample and a tumour tissue sample will be collected and stored at the Princess Alexandra Hospital tissue bank. Tissue will be taken from tumour removed to confirm diagnosis and the blood sample will be collected as part of routine blood tests that the patient will have as part of the conduct of the study. To protect the privacy of the patient, any information on the biological tissue that may identify the patient will be removed and replaced with a unique identification number only. Any future research will only be done after approval by a research ethics committee and all patient information and samples will remain de-identified.


3.0 TRIAL OBJECTIVES AND ENDPOINTS

3.1 Hypothesis

The addition of chemotherapy to high dose palliative radiotherapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with symptoms predominantly due to intrathoracic disease and who have good performance status (PS) but are not suitable for radical chemo-radiotherapy:

maximises intrathoracic symptom palliation (both the extent of improvement and its duration),

leads to an improvement in QOL, and

is associated with acceptable toxicity, compared with high dose palliative radiotherapy alone.

3.2 Objectives

3.2.1 Primary Objective To compare, in this group of patients, high dose palliative radiotherapy (HDPRT) versus concurrent chemotherapy and HDPRT (C-HDPRT), with respect to

The relief of dyspnoea, cough, haemoptysis and chest pain as assessed by change in total symptom burden from baseline to six weeks after the completion of treatment.

Response for each component symptom separately (dyspnoea, cough, haemoptysis, chest pain)

3.2.2 Secondary Objectives To compare the two regimens in terms of

Dysphagia during treatment

Thoracic symptom response rate

Duration of thoracic symptom response

QOL

Toxicity

Progression-free survival

Overall survival

3.2.3 Exploratory/Tertiary Objectives

To determine how much improvement in QoL and symptom palliation would be necessary to make the inconvenience due to the longer duration of radiotherapy of C-HDPRT worthwhile, relative to HDPRT. This objective will be addressed in the Patient Preferences Substudy.

Analyse serum protein glycosylation changes and exosomes to identify potential biomarkers of disease response and progression

Prospectively collect and bank tumour tissue and blood samples from this cohort of patients for future evaluation of potential biological markers


3.3 Endpoints

3.3.1 Primary Endpoints

Change from baseline at 6 weeks after treatment in the Intrathoracic Symptom Burden Index (see definition, section 11.1);

Change from baseline at 6 weeks after treatment in each of the component symptoms, dyspnoea, cough, haemoptysis and chest pain.

3.3.2 Secondary Endpoints

Profile of change from baseline of Intrathoracic Symptom Burden Index, and of component symptoms, by time (6 weeks, 3, 6, 12, 24 months)

Area under curve (AUC) of dysphagia (LC13, Q37) during treatment

Thoracic symptom response rate and response duration

Physician’s rating of cough, dyspnoea, haemoptysis and chest pain, summed into a symptom index

Physician’s rating of performance status (Karnofsky) (Appendix 5) and QOL (Spitzer) (Appendix 6)

The area under the curve (AUC) of the overall QOL measure (QLQ-C30, Q29, Q30) (Appendix 8), from baseline to the return to baseline value or to last follow-up

Profiles of all domains and items measured by the QOL instruments will be similarly assessed

Toxicity measured by NCIC CAE v 3.0

Tumour response

Progression-free survival

Overall survival


4.0 TRIAL DESIGN 4.1 Trial design This is a multi-centre, two-arm, randomised Phase III trial. All eligible patients will be stratified according to tumour stage, histology, major chest symptoms and treating institution and will be randomised in the ratio of 1:1 to either: ARM A (control arm): High dose palliative RT (HDPRT) alone (36Gy/12 fractions, 4-5 fractions/week) or ARM B (investigational arm): Chemotherapy + HDPRT (40Gy/20fractions, 4-5 fractions/week + IV cisplatin 20mg/m2 days 1, 8, 15, 22 + IV vinorelbine 25mg/m2 days1, 8, 22). (C + HDPRT) 4.2 Total Participant Accrual The total participant accrual for this trial will be 130. The accrual period is expected to be 41 months and total study duration 55 months.

5.0 PARTICIPANT SELECTION

Patients may be included in the trial only if they meet all of the inclusion and none of the exclusion criteria. No exceptions, waivers or exemptions will be granted.

5.1 Inclusion Criteria

Aged 18 years or older

ECOG PS 0-1,

Histological or cytological proven stage III or IV NSCLC of any subtype: Adenocarcinoma, Squamous Cell Carcinoma (SCC), NSCLC Not Otherwise Specified (NOS) or Other (including Large Cell Undifferentiated).

Symptoms due to intrathoracic disease (at least one of cough, dyspnoea, haemoptysis, chest pain),

Patients with Stage III NSCLC not suitable for radical chemo-radiotherapy (due to concurrent medical illness, weight loss > 10% or tumour volume too large for radical radiation fields (e.g. dose constraints for organs at risk cannot be met using radical radiation fields or at the discretion of the investigator) or

Patients with metastatic disease of any site or extent who have symptoms predominantly due to intrathoracic disease.

Planned for HDPRT to achieve local control and symptom relief

Adequate organ function;

o Bone marrow: Haemoglobin (Hb) ≥ 100g/l, Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Platelet count ≥ 100 x 109/L

o Hepatic: Serum bilirubin ≤ 1.0 x upper limit of normal (ULN), AST/ALT ≤ 2.0 x ULN, ALP ≤ 2.5 x ULN.

o Renal: Creatinine Clearance ≥ 55 ml/min (Cockcroft-Gault formula – see appendix 3)


No prior therapy for NSCLC

Able to commence Radiotherapy no later than 6 weeks, but preferably within 4 weeks from the time of participant randomisation. It is preferred that RT be commenced on a Monday or Tuesday.

Has provided written informed consent to participate in this trial

Participants capable of childbearing are using adequate contraception

Available for follow-up for a minimum of 3 months.

5.2 Exclusion Criteria

Receiving treatment with another investigational agent

History of any other cancer (except non-melanomatous skin cancer or carcinoma in situ of the cervix) unless in complete remission and off all therapy for that cancer for at least 3 years.

Women who are pregnant or lactating

Previous radiotherapy to the area to be treated, at any time.

Significant medical conditions which in the opinion of the investigator would compromise the planned delivery of the chemotherapy and radiotherapy or which may be potentially exacerbated by these modalities

6.0 REGISTRATION AND RANDOMISATION

6.1 Screening and Registration

The Investigator should ensure that all of the following requirements are met prior to patient enrolment:

The patient meets all inclusion criteria and none of the exclusion criteria apply.

The patient has signed and dated all applicable consent forms.

All baseline assessments and investigations have been performed and recorded in the patient’s medical records (i.e. source documents).

The registration and eligibility Case Report Form(s) (CRF) have been completed, signed and dated by the Investigator

6.2 Randomisation

Following registration the participant will be randomised to one of the following arms: ARM A (control arm): High dose palliative RT (HDPRT) alone (36Gy/12 fractions, 4-5 fractions/week) - or ARM B (investigational arm): Chemotherapy + HDPRT (40Gy/20fractions, 4-5 fractions/week + IV cisplatin 20mg/m2 days 1, 8, 15, 22 + IV vinorelbine 25mg/m2 days 1, 8, 22) (C + HDPRT) Please refer to the TROG11.03 Data Management Procedures document or contact the Central Trial Coordinator for registration/randomisation procedures.


6.3 Central Trial Coordinator Contact Details

Cassie Freriechs Clinical Trials Unit Dvision of Cancer Services Princess Alexandra Hospital Ipswich Road, Woolloongabba Qld 4102 T: +61 (0)7 3176 2498 F: +61 (0)7 3176 1929 - trial correspondence only, NOT CRFs E: [email protected] TROG Teleform Fax : (0)2 4014 3618 – fax submission of all CRFs Trial Coordinating Centre Office hours: Monday to Friday 08.30am to 5.00pm Australian EST

7.0 TREATMENT REGIMEN

7.1 Radiotherapy

7.1.1 Treatment aim and rationale

High dose palliative radiotherapy will be delivered in both treatment arms. The RT regimen employed in the control arm (36Gy/12f) is derived from the Medical Research Council LU13 trial(12). This regimen is a widely employed palliative radiotherapy schedule used in good PS patients with l locally advanced disease not suitable for curative regimens.

The RT regimen employed in the investigational arm (40Gy/20f) is derived from the preceding TROG 03.07 Phase II trial which demonstrated superior response, PFS and OS without a clinically significant increase in toxicity or QOL impairment for this regimen.

7.1.2 Treatment Schedule

Radiotherapy must commence no later than 6 weeks, but preferably within 4 weeks from the time of participant randomisation. Participants Randomised to Arm A will receive 36Gy/12f, 2Gy/f delivered 4-5 times per week for 2.5-3 weeks. Participants randomised to Arm B will receive 40Gy/20f delivered 4-5 times per week for 4-5 weeks.


7.1.3 Planning Simulation

The patient should be simulated in the supine position. An immobilisation device may be used depending on the policy of the trial site. CT planning with or without contrast is mandatory for all participants. The scan thickness should be 5 mm or less and the scan should extend from the cricoid cartilage superiorly to the inferior border of the liver. A treatment planning FDG PET/CT scan or fusion with an FDG PET scan is encouraged for planning. The use of a method to account for tumour motion may be employed depending on the policy of the trial site. The use of motion management is not mandatory for this trial but if used, the method is to be recorded.

7.1.4 Target Volume definitions and dose constraints

7.1.4.1 Target Volumes

The Gross Tumour Volume (GTV) is defined as the primary tumour and clinically involved loco-regional lymph nodes seen either on planning CT scan (>1cm short axis diameter) or pre-treatment FDG PET scanning. Standardised Naming: TROG_GTV

The Clinical Target Volume (CTV) is defined as the GTV plus 0.5cm in all directions. Elective treatment of the mediastinum and supraclavicular fossae will not be performed. Standardised Naming: TROG_CTV

The Planning Target Volume (PTV) is defined as the CTV plus 1.0cm in all directions. Standardised Naming: TROG_PTV4000 or TROG_PTV3600

All volumes will be defined on the CT slices using a 3D planning system. The following constraints apply to the PTV:

PTV Constraint

D98 (Near Minimum) - Dose to 98% of PTV

≥95% of prescribed dose

D2 (Near Maximum) – Dose to 2% of PTV

≤107% of prescribed dose

Table 3: Dose Constraints to PTV

7.1.4.2 Field Borders The PTV is to be treated with 3-D conformal radiation fields shaped to deliver the specified dose while restricting the dose to the normal tissues.


7.1.5 Normal tissue contouring and dose constraints

The following organ at risk dose constraints are mandated for all trial participants Arm A

Normal Tissue

Standardised Name

Constraint

Spinal Cord SpinalCord Maximum point dose ≤ 36Gy

Left and Right Lung minus the PTV

BilatLung-PTV V18 (volume of right and left lung minus PTV receiving 18Gy) ≤35%

V27 (volume of right and left lung minus PTV receiving 27Gy) ≤ 25%

Mean Lung Dose < 18Gy

Arm B

Normal Tissue

Standardised Name

Constraint

Spinal Cord SpinalCord Maximum point dose ≤ 40Gy

Left and Right Lung minus the PTV

BilatLung-PTV V20 (volume of right and left lung minus PTV receiving 20Gy)≤ 35%

V30 (volume of right and left lung minus PTV receiving 30Gy) ≤25%

Mean Lung Dose < 20Gy

Tables 4 & 5: Dose Constraints to Spinal Cord and Lungs (Arms A & B)

7.1.6 Dose prescription and fractionation:

7.1.6.1 Total Dose & Dose per Fraction

Arm A 36 Gy in 12 fractions, 3Gy/fraction, 4-5 fractions per week (once daily). Arm B 40 Gy in 20 fractions, 2Gy/fraction, 4-5 fractions per week (once daily). 7.6.1.2 Dose to Reference Point Dose is to be prescribed such that the dose constraint criteria outlined in Table 3 for the PTV are met. 7.1.6.3 Treatment Duration

Arm A RT will be given over 2.5 weeks.

Arm B RT will be given over 4 weeks. If RT is interrupted, the chemotherapy will also be delayed.

In the event of a treatment interruption for any reason, the missing dose fraction(s) should be made up at the end of the treatment course. B.D. fractionation is not permitted.

The reason for any treatment interruption must be documented.


7.1.7 Treatment Planning and Dosimetry Inverse planned IMRT techniques are not permitted in this trial 7.1.7.1 Planning System Requirements Treatment planning will be carried out with a 3D planning system which shall have, as a minimum, the following capabilities:

Able to handle at least 40 axial CT slices at 256 x 256 pixel resolution.

Allows definition of multiple structures in 3D from CT data.

Provides a 3D dose calculation algorithm (e.g. convolution / superposition algorithm) capable of performing calculations which account for variations in scatter in the presence of 3D-(CT) defined heterogeneities.

Can provide a permanent record of each treatment plan, both in electronic form (data backup) and hard copy.

Can provide hardcopy of superimposed isodose distributions on axial CT images (sagittal and coronal planes desirable).

Can provide digitally reconstructed radiographs (DRRs) with superimposed target volume, critical structure contours and treatment aperture.

Provides planning data export in DICOM RT format.

Treatment planning guidelines include:

An isocentric technique will be used

All fields are delivered each day

Treatment is delivered with a linear accelerator with ≥ 6 megavoltage photons.

7.1.7.2 Beam Arrangements The PTV is to be treated with any combination of coplanar or non-coplanar 3-dimensional conformal fields shaped to deliver the specified dose while restricting the dose to the normal tissues. 7.1.7.3 Shielding & Customised Blocks Customised shielding should be used to protect normal tissues outside of the target volume 7.1.7.4 Compensation and Heterogeneity Corrections All radiation doses will be calculated with inhomogeneity corrections that take into account the density differences within the irradiated volume.


7.1.7.5 Dose Distribution/Reporting External Beam Radiation Therapy Dose reporting requirements follow ICRU reports 50, 62 and 83 for photons. Dose - volume metrics from the dose-volume histogram data (DVH) are required for all trials. A DVH must be generated at the treatment planning system for each target structure and each contoured organ at risk. DVH format and labelling of all structures must be clear. The following dose volume parameters should be reported for all target volumes:

D98 near-minimum dose: defined as the dose to 98% of the target volume.

D2 near-maximum dose: the absorbed dose received by 2 % of the target volume

Other relevant dose-volume metrics to be reported:

The total dose in Gray (Gy) to be received to a given reference point must be stated where applicable.

7.1.8 Treatment Verification and Delivery

Treatment position should be replicated from simulation. Electronic portal images should be taken as per departmental protocol.

7.1.9 QA Reporting

Centres should provide the below data for all participants selected for QA review. This data should be submitted for review via the Central Quality Management System (CQMS) as zipped files. Information on CQMS user accounts and training are available on the TROG website (www.trog.com.au). The participant data will be de-identified at the point of upload to CQMS. The participant name and ID will be replaced with the trial identifier and the participant reference, eg 11.03 ABC123. 7.1.9.1 Digital Export of Radiotherapy Treatment Plan An electronic export of the radiotherapy treatment plan from the treatment planning system is required. The acceptable file format is DICOM-RT; contact TROG QA for further information.

Plan export guidelines are available on the TROG website, www.trog.com.au, Professionals, QA programme. The guidelines cover the latest versions of all major treatment planning systems.

Treatment Re-Plans: A plan sum MUST be created for all cases that have commenced treatment and subsequently required a re-plan. The plan sum must include the dose from the original plan (i.e. the proportion of dose that was delivered) and the remaining dose delivered from the re-plan. An accurate DVH for all structures and target volumes representing the proportion of dose from the original plan and the re-plan must be created

http://www.trog.com.au/



for the purpose of review. The plan sum MUST be exported from the planning system and submitted for review.

This electronic export must be in absolute dose (Gy) and include all relevant data relating to:

CT dataset, or other imaging dataset used for plan calculation, ensuring all

files are included.

Structure files, ensure all structures including CTV/PTVs are exported and named according to protocol specifications. There will only be one file if the same structure set has been used for all phases, generally prefixed RS.

Plan files, ensure the plan is calculated to the correct specifications and approved. There will be one plan file for each phase, generally prefixed RP.

Dose files, ensuring the dose matrix is inclusive of all structures. There will be one dose file for each phase, generally prefixed RD.

All data relating to the Radiotherapy Treatment Plan export must be uploaded into CQMS using the [RT Plan Upload] function on the checklist. 7.1.9.2 Verification images of the isodose distribution In addition to the radiotherapy plan export, a screen capture from the planning system (JPEG image) for each phase of treatment is required. It is essential the screen capture follows the format below; as it will be used to verify the accuracy of the electronic plan import into the plan review software. Verification images must be combined into a single zipped folder and uploaded via CQMS using the [Other Upload] function in the checklist.

Format De-identified screendump (JPG image) from the planning system demonstrating the isodose distribution. This image must include all 3 viewing planes, i.e. sagittal, axial and coronal planes, at the intersection of a relevant point (e.g. ICRU reference point, isocentre, CT reference) within the central part of the PTV.

The CT co-ordinates of this point (x, y, z) must be visible.

Ensure isodose lines are in absolute dose (Gy) and are clearly displayed (no colourwash).

For all multi-phase plans, a verification image must be provided demonstrating the composite dose.

Each screendump (including the composite verification image) must also demonstrate the absolute maximum dose (Gy) of the plan. Alternatively a separate screendump must be created to demonstrate the maximum dose.


7.1.9.3 Dose Volume Histogram De-identified screendump of the Dose Volume Histogram (DVH) demonstrating all regions of interest and dose statistics. These images are required for all electronically submitted plans to verify accurate import and display of DVH data. They must be provided in colour and large enough to assess each structure.

For all multi-phase plans, a screendump of the DVH demonstrating the composite dose from all relevant phases/prescriptions must be provided.

7.1.9.4 Supplementary data This information can be exported from the oncology information management system:

PDF copy of Treatment Plan Summary – including all field information e.g. number of beams, shielding, monitor units, gantry angles etc.

Copy of the treatment prescription. As a minimum the prescription MUST indicate for each treatment phase, the total prescribed dose, number of fractions, dose per fraction and any other additional prescriptive factors e.g. bolus, whether the dose is prescribed to a volume/point/covering isodose etc. Electronic prescriptions are accepted provided all relevant data is evident.

Daily Dose Record including dates of treatment delivery and total delivered dose.

Imaging Log including verification of dates for imaging taken during treatment.

7.1.10 Treatment Equipment Specifications/Physical Factors

Participants will be treated on megavoltage equipment i.e. linear accelerator beams with minimum nominal energy of 6MV. Source Axis Distance (SAD) should be at least 100cm. Electrons, particles and implants are not permitted.


7.2 Chemotherapy

7.2.1 Treatment Schedule

Arm A Patients will not receive concurrent chemotherapy, only radiotherapy of 36Gy/12f

Arm B Patients will receive chemoradiotherapy: IV cisplatin 20mg/m2 days 1, 8, 15, 22 of RT plus IV vinorelbine 25mg/m2 days 1, 8 and 22 of RT.

It is preferred that Chemotherapy be administered 2-4 hours before RT.

ARM A ARM B

Weeks

Days

1

1

2

8

3

15

4

22

1

1

2

8

3

15

4

22

Cisplatin X X X X

Vinorelbine X X X

Table 6: Chemotherapy Treatment Schedule (Arms A & B)

7.2.2 Chemotherapy Administration and Dosage

7.2.2.1 Vinorelbine

Drug description: Vinorelbine tartrate is a semisynthetic vinca alkaloid with anti-tumor activity, which interferes with microtubule assembly. Chemical name: 3',4'-didehydro-4'- deoxy-C'- norvincaleukoblastine [R-(R,R)-2,3 dihydroxybutanedioate (1:2)(salt)]. Molecular formula: C45H54N4O8.2C4H6O6. MW: 1,079.12. CAS: 125317-39-7.

Vinorelbine is a white to yellow or light brown amorphous powder. The aqueous solubility is > 1,000 mg/mL in distilled water. The pH of Navelbine injection is approximately 3.5. Formulation: Active. Vinorelbine tartrate. Inactive. Nitrogen, water for injections. Drug formulation: Vinorelbine; single use vials; Pack: 10 mg /1 mL (single-use) Pack: 10 mg /1 mL (single-use) Pack: 50 mg /5 mL (single-use) Pack: 50 mg /5 mL (single-use) Preparation for administration.

Navelbine (vinorelbine) injection must be diluted in either a syringe or intravenous bag using one of the recommended solutions. The volume of dilution depends on the mode of administration.

Diluted Navelbine may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5 to 30 deg. C.

Syringe. The calculated dose of Navelbine should be diluted to a concentration between 1.5 and 3.0 mg/mL. The following solutions may be used for dilution: Dextrose 5% Injection USP and Sodium Chloride 0.9% Injection USP.


Intravenous bag. The calculated dose of Navelbine should be diluted to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution: Dextrose 5% Injection USP; Sodium Chloride 0.9% Injection USP; Sodium Chloride 0.45% Injection USP; Dextrose 5% and Sodium Chloride 0.45% Injection USP; Ringer's Injection USP and Lactated Ringer's Injection USP.

After diluting Navelbine in normal saline or dextrose solution, the shelf life in the clear glass vials or in PVC perfusion bags is 24 hours at storage below 30 deg. C.

Navelbine should not be diluted in alkaline solutions due to the risk of precipitation. Navelbine should not be mixed with other agents. Navelbine is not absorbed to or affected by either PVC or clear neutral glass.

To reduce microbiological hazard, use as soon as practicable after preparation. If storage is necessary, hold at 2 to 8 deg. C for not more than 24 hours.

Storage Store at 2 to 8 deg. C. (Refrigerate. Do not freeze.) Protect from light. 7.2.2.2 Cisplatin Drug description: Cisplatin is an antineoplastic agent with biochemical properties similar to those of bifunctional alkylating agents. The drug inhibits DNA synthesis by producing intrastrand and interstrand crosslinks in DNA. Protein and RNA synthesis are also inhibited to a lesser extent. Cisplatin does not appear to be cell cycle specific. A member of the platinum alkylating agents. Formulation: Active. Cisplatin. Inactive. Mannitol BP 1 mg/mL, Sodium Chloride BP 9 mg/mL, Water for Injections BP; preservative free.

Pack: 10 mg /10 mL Brand substitution is permitted. Pack: 50 mg /50 mL Brand substitution is permitted. Pack: 100 mg /100 mL Refer: MIMS

Preparation of cisplatin administration. Cisplatin Injection should be added to 1 L of sodium chloride IV infusion 0.9%.

Storage Store at 15 to 25 deg. C. Do not refrigerate. Do not freeze. Protect from light.

Stability

Cisplatin 0.15 mg/mL in sodium chloride IV infusion 0.9% is chemically stable for 24 hours when stored at room temperature and protected from light. The solution does not contain any antimicrobial preservatives and to avoid microbial contamination hazards, infusion should be commenced as soon as practicable after preparation. Infusion should be completed within 24 hours of preparation and any residue discarded.

7.2.3 Dose definition and number of cycles

Doses will be as follows: Cisplatin: 20mg/m2, days 1, 8, 15, 22 of RT Vinorelbine: 25mg/m2, days 1, 8, 22 of RT,

Body surface area will be calculated on actual body weight. Patients with a BSA 2.2m2, will have their doses calculated using a BSA of 2.2 m2.


Chemotherapy will only be given concurrently with radiotherapy.

7.2.4 Technique of drug administration and premedication

Premedication within 30 min of chemotherapy IV Metoclopramide10mg IV Dexamethasone 8mg IV 5HT3 antagonist PO Aprepitant 125mg (as per institutional practice)

Chemotherapy: Cisplatin dissolved in 500ml Normal Saline over 1 hour. Vinorelbine dissolved in 100ml of Normal Saline, followed by 100ml of N Saline over 5-

10 minutes. It is preferred that chemotherapy be given 2-4 hours before the delivery of the radiation fraction on that day.

Supportive medication post-chemotherapy dose: The following standard post-chemotherapy antinauseant therapy will be given: Metoclopramide: 10mg, po, q 6-8hr, prn, Dexamethasone: 4mg, po, daily for 1 day post chemotherapy 5HT3 antagonist: po, for 1 day post chemotherapy. Aprepitant: po 80mg daily for 2 days (as per institutional practice)

7.2.5 Sequence of timing of drug administration relative to radiotherapy: (Arm B)

Patients will be treated with chemoradiotherapy consisting of the following schedule:

Arm B

Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

RT (2Gy/f) X X X X X X X X X X X X X X

Cisplatin X X X

Vinorelbine X X

Arm B

Days 19 20 21 22 23 24 25 26

RT (2Gy/f) X X X X X X

Cisplatin X

Vinorelbine X

Tables 7 & 8: Sequence of Chemotherapy & Radiotherapy (Arms A & B)

https://www.mimsonline.com.au/Search/QuickSearch.aspx?ModuleName=Product%20Info&searchKeyword=Aprepitant&FieldName=GenericName

https://www.mimsonline.com.au/Search/QuickSearch.aspx?ModuleName=Product%20Info&searchKeyword=Aprepitant&FieldName=GenericName


Arm B: Radiotherapy will be given at a total dose of 40Gy in 2 Gy fractions over 4 weeks, i.e. 20 fractions.

Vinorelbine will be given on days 1, 8, and 22 of radiotherapy according to the above schema.

Cisplatin will be given on days 1, 8, 15 and 22 of radiotherapy according to the above schema.

7.2.6 Duration of treatment: Arm B

Treatment will be over the 4 weeks of radiotherapy. Induction chemotherapy prior to radiotherapy and consolidative chemotherapy post radiotherapy will not be allowed

7.2.7 Toxicity criteria expected effects and their timing: Arm B

All acute toxicities will be based upon the NCIC CAE v 3.0 The expected effects of the chemotherapy include the following:

Cisplatin: 1. Acute (within 24 hours) and delayed emesis (within 48 hours) 2. Myelosuppression, within 7-10 days 3. Neuropathy at a cumulative dose > 400mg/m2, (unlikely with this regimen) 4. Renal toxicity, acute within few days, potentially associated with hypomagnesaemia

and hypokalaemia (unlikely with this regimen).

Vinorelbine: 1. Mild acute nausea and vomiting 2. Thrombophlebitis, within a few days 3. Myelosuppression within 7 days. 4. Neuropathy, within few weeks. 5. Constipation

7.2.8 Dose modification: Arm B

The following schema will be used for dose reduction of chemotherapy. Patients requiring more than 2 dose reductions will discontinue chemotherapy.

Radiotherapy will continue. Dose reductions are permanent. There will be no intrapatient dose escalation or re-

escalation after dose reduction.


Time Grade Vinorelbine (D 8, 22)

Cisplatin (D 8, 15,22)

Neutropenia

Febrile neutropeniaa Omit & next dose by 2 levels if

ANC recovers to > 1.0 Omit & next dose by 1 level if ANC recovers to > 1.0

On treatment day ANC < 0.50 x 109/L Omit & next dose by 2 levels if

ANC recovers to > 1.0 Omit & next dose by 1 levels if ANC recovers to > 1.0

ANC 0.50 – 0.99 x 109/L Omit dose and reduce next

dose by 1 level if ANC recovers to > 1.0

Omit dose, and treat at same dose if ANC recovers to > 1.0

ANC 1.00 – 1.49 x 109/L Reduce by 1 level Treat at same dose

Thrombocytopenia

On treatment day Plt < 10 x 109/L or

Plt 10 – 49 x 109/L &

bleeding

Omit & reduce next dose by 2 levels if plt recovers to > 50

Omit & reduce next dose by 1 level if plt recovers to > 50

Plt 10 – 49 x 109/L

without bleeding Omit dose and reduce next dose by 1 level if plt recovers to > 50

Omit dose and treat at same dose if plt recovers to > 50

Plt 50 – 99 x 109/L Reduce by 1 level Treat at same dose

Neurological or ototoxicity

Worst grade Grade 3 or 4 Cease chemotherapy Cease chemotherapy

On treatment day Grade 2 Reduce by 2 levels Reduce by 1 level

Renal toxicity

Worst grade Se creat 3.0 x ULN Cease chemotherapy Cease chemotherapy

On treatment day Se creat > 1.5 – <3.0 x ULN & creat clear < 45 ml/min

b

Omit dose and reduce next dose by 1 level if creat recovers to < 1.5xULN & creat clear to > 45

Omit dose and reduce next dose by 1 level if creat recovers to < 1.5 xULN & creat clear to > 45

Se creat > 1.5 – <3.0 x ULN & creat clear > 45 ml/min

No change No change

Se creat < 1.5 x ULN & creat clear < 45 ml/min

Omit dose and reduce next dose by 1 level if creat clear recovers to > 45

Omit dose and reduce next dose by 1 level if creat clear recovers to > 45

Oesophageal/ pulmonary toxicity in radiation field c

Worst grade Grade 3 & 4c Omit dose. Recommence with

1 dose level reduction if recovers to grade 2 or less

Omit dose. Recommence with 1 level dose reduction if recovers to grade 2 or less

On treatment day Grade 2 Reduce dose by 1 level Reduce dose by 1 level

Other clinically significant non-haematological toxicities outside the radiation fieldd

Worst grade Grade 4 Cease chemotherapy Cease chemotherapy

On treatment day Grade 3/2 Omit dose and reduce next dose by 1 level if recovers to grade 1

Omit dose and reduce next dose by 1 level if recovers to grade 1

Table 9: Schema for dose reduction of chemotherapy aFever of unknown origin without clinically or microbiologically documented infection with ANC < 1.0 x

109/L and temperature > 38.5°C.

bCreatinine clearance may be derived from serum creatinine using Cockcroft-Gault formula.

c Radiotherapy, together with chemotherapy, will be suspended if the patient experiences grade 3 or 4

radiation-associated toxicities (e.g. oesophagus, lung, skin, heart). Radiation therapy & chemotherapy (with a 1 dose level reduction) will recommence once reactions have improved to grade 2 or better.

dPlease discuss with Trial Chair. Excludes alopecia and nausea vomiting that has not been

adequately treated by standard anti-nauseant medication, including 5HT3 antagonists, cyclizine etc.


The dose levels are as follows:

Dose level Vinorelbine (mg/m2) Day 1, 8, 22

Cisplatin (mg/m2) Day 1, 8, 15, 22

Starting dose level 25 20

Dose level -1 20 15

Dose level -2 15 N/A

Table 10: Chemotherapy Dose Modifications

7.2.9 Calculation of body surface area

Body surface area (BSA) will be calculated using the following formula: BSA (m2) = 0.007184 (W0.425 x H 0.725) Where W is actual body weight in kilograms and H is height in centimetres. In the event of a weight change of ≥ 10% from time of randomisation, treatment doses should be re-calculated. Where the calculated BSA is over 2.2m2, then the BSA used for dose calculation should be capped to 2.2m2.

7.2.10 Non-permitted medications/treatments

Investigators can prescribe medications/treatments that are deemed necessary for the well-being and overall treatment of the trial participant. However, there are certain types of medication or therapies that are not-permitted while on trial treatment including investigational drugs, targeted therapy and concurrent cytotoxic chemotherapy other than defined by the protocol. The dates and dosage of all prescription and non-prescription medications must be documented in the patient’s medical record and transcribed onto the relevant CRF.

7.2.11 Drug Supply

The chemotherapy drugs will be ordered by the medical staff of the medical oncology department of the respective site, from the institutional pharmacy. The institutional pharmacy will procure the drugs though the Pharmaceutical Benefit Scheme.

7.2.12 Investigator’s Brochure

The investigational products (Cisplatin and Vinorelbine) are marketed drugs and their pharmacology is widely understood by clinicians. In this trial, both drugs are used for an approved indication. An Investigator’s Brochure (IB) is therefore not necessary for the purpose of this trial. The product information leaflets including current, comprehensive, and detailed information will be provided and should be filed in the Trial Master File at each Trial Site.

7.2.13 Monitoring Toxicity and Modifications

Bloods will be taken on day 1 of each week of concurrent chemo-radiotherapy for FBE, and biochemistry (U + E + Creatinine). Modifications of these parameters may lead to adjustment to the combined therapy as outlined in section 7.2.8 above.


During chemoradiotherapy, Creatinine clearance estimation (Cockcroft-Gault formula) will be calculated weekly if there is an increase in serum creatinine above baseline or a decrease in body weight in excess of 10% of baseline.

8.0 TRIAL PARTICIPANT ASSESSMENTS The following assessments will occur during the trial. A table of assessments is provided in the appendices (Appendix 6)

8.1 Pre-Registration Assessments

The following assessments must be performed within 4 weeks prior to registration.

Confirmation of disease site and stage via o CT Chest and Upper Abdomen o CT Brain (if adenocarcinoma is clinically indicated), or o FDG-PET scan if performed (this is not mandatory)

Medical history

ECOG performance status

Karnofsky performance status

Physical examination

Current weight and height

Bloods for full blood examination (FBE)

Bloods for serum biochemistry (urea, creatinine, electrolytes, liver function tests

Pregnancy Test (women of child-bearing potential should be performed within 7 days of treatment starting.

Respiratory function tests (at least FEV1/FVC)

Quality of life questionnaires: patient self completed QLQ-C30 and QLQ-LC13 and a physician rated Spitzer Index (performed at the time of registration). Patient must complete QoL forms after they provided informed consent and before they know which ARM they have been randomised to.

8.2 Pre-Treatment Assessments

The following tests must be performed within 2 weeks prior to protocol treatment for Arm A and B participants

Bloods for full blood examination (FBE)

Bloods for serum biochemistry (urea, creatinine, electrolytes, liver function tests)

Physical examination

Current weight and height


Toxicity assessment using NCIC CTCAE v3.0

Concomitant medications recorded

Quality of life questionnaires: patient self completed QLQ-C30 and QLQ-LC13 and a physician rated Spitzer Index.

Peripheral blood and tumour samples sent for banking

Peripheral blood sent for Exosomes Sub-Study

Patient preferences questionnaire (refer to section 9)* * Patient preferences questionnaire can be done any time before protocol treatment commences


8.3 Assessments During Treatment

During treatment, the following assessments will be performed weekly: 8.3.1 Arm A Participants

Physical Examination


Weight measurement

Toxicity assessment (NCIC CTCAE v 3.0)

Adverse events

Quality of life: QLQ-C30, QLQ-LC13

Physician rated Spitzer index

8.3.2 Arm B Participants

Bloods for full blood examination (FBE)*

Bloods for serum biochemistry (urea, creatinine**, electrolytes, liver function tests)*



Weight measurement**


Adverse events



* Only required For those patients receiving chemotherapy. It is recommended that bloods be taken on day 1 of each week

** If there is an increase in serum creatinine above baseline or a decrease in body weight in excess of 10% of baseline a creatinine clearance estimation is required (see section 7.2.13)

8.4 End of Treatment Assessments

8.4.1 Arm A Participants (Week 3)

Quality of life (QLQ-C30, QLQ-LC13)

Toxicity assessment (NCIC CTCAE v3.0)

Physician rated Spitzer index 8.4.2 Arm B Participants (Week 4)


Toxicity assessment (NCIC CTCAE v3.0)

Physician rated Spitzer index 8.4.3 Arm A and Arm B Participants (end of Week 4)

Concomitant medications recorded


8.5 Follow-up Assessments

For Arm A and B participants: Two weeks and six weeks post the completion of treatment, the following assessments will be performed:



Quality of life (QLQ-C30, QLQ-LC13),


Concomitant medications recorded (including commencement of chemotherapy or targeted agents)

At 6 weeks post treatment, a CT scan of Chest and Upper Abdomen +/- PET scan will be performed. At three months post treatment, the following assessments will be performed:




Physician-rated Spitzer index

CT scan +/- PET


At six months and every three months thereafter until progression

Clinical assessment including re-staging with CT scan Chest and Upper Abdomen or earlier if clinically indicated






8.6 Disease Progression Assessments:

Clinical assessment including re-staging with CT scan Chest and Upper Abdomen +/- CT Brain, +/- PET





8.7 Completion of Quality of Life (QoL) Questionnaires

The primary endpoint in this study is to record the changes in participant’s symptoms from baseline at the various scheduled assessments as detailed above. The presence and severity of these symptoms are scored using four QoL questionnaires: EORTC QLQ-C30 and LC13, Spitzer Index and Karnofsky Scale. The Spitzer Index and Karnofsky Scale are completed by the Clinician, while the EORTC QLQ-C30 and LC13 questionnaires are completed by the participants at the time-points detailed above. It is very important that the QOL assessments are completed within acceptable time limits surrounding the scheduled assessments. The clinician-completed Spitzer Index and Karnofsky Scale are just as important as the patient-reported QOL forms, even more so when the patient fails to complete the QOL questionnaire. The recommended acceptable time limits for completion of QOL assessments are;

Assessment Time Point Beginning of Acceptable

time limit End of Acceptable time limit

1. Pre-Registration Date of signing consent Date patient made aware of treatment arm to which they have been assigned

2. Pre-Treatment Date patient made aware of treatment arm to which they have been assigned

Date of first radiation dose

3. During Treatment Day of treatment Before next treatment (eg If patient given QOL form on Monday then QOL should be completed before treatment on Tuesday)

4. End of Treatment Date of last treatment Five days after last treatment

5. Two weeks after end of treatment

1 week after end of treatment 3 weeks after end of treatment

6. Six weeks after end of treatment

Five weeks after end of treatment

Eight weeks after end of treatment

7. Three months after end of treatment

Nine weeks after end of treatment

Eighteen weeks after end of treatment

8. Six months after end of treatment

Five months after end of treatment

Nine months after end of treatment

Table 11: Acceptable submission timeframes for QoL Data In some cases, participants will not be able to attend the clinic for one (or more) of their scheduled visits, however it is still very important to be able to capture the required QoL data. The following section describes instances that might trigger alternative completion methods of QoL and those methods approved for implementation as part of the TROG 11.03 PLUNG Trial.


8.7.1 Triggers for alternative Completion Only those instances described below can trigger the process for alternate completion of QoL Questionnaires (EORTC QLQ-C30 and LC 13).

Patient notifies the Trial Coordinator and/or their treating Clinician prior to their scheduled visit, that they will not be attending and another visit is not rescheduled prior to the next scheduled visit.

Patient has not notified the Trial Coordinator and/or their treating Clinician prior to their scheduled visit that they cannot attend i.e. participant does not turn up.

8.7.2 Alternative Completion Methods When a patient does not complete the QoL assessment, as described above, the Trial Coordinator has two options:

Primary Alternative: Ask the participant to complete the QoL assessments via post OR

Secondary Alternative: Ask the participant to complete the QoL assessments over the phone

8.7.2.1 Completion via post If a patient is required to complete a QoL assessment at any stage during the trial or follow-up stage and return by post the trial site will ensure the following;

It will be explained to the patient at the time of obtaining consent that if they are unable to attend the trial site for a visit/s they will be asked to complete the QoL assessment by mail

Full contact details including telephone numbers will be obtained at registration of patient.

If the Trial Coordinator/Investigator is notified that the patient will not be attending their scheduled visit or the patient does not turn up, the Trial Coordinator will contact the patient and ask if they are willing to complete the QoL assessments via post and return to the trial site in a reply paid envelope.

The QoL assessments (EORTC QLQ-C30 and QLQ-LC13), instructions and reply paid envelope will be mailed by express post for completion to the patient. These documents are to be sent to the participant prior to or as close to as possible their scheduled assessment date in order to capture the required data for primary endpoint analysis.

The trial coordinator will telephone the patient within 2 working days of sending the QoL assessments to ensure that they were received. At this stage if they have not received the assessment the trial coordinator will attempt to complete this over the telephone. In order for the data to remain valid to the specified assessment time point, all efforts should be made to have the form completed (and therefore dated) according to table 11. Acceptable submission timeframes for QoL Data, for each specified assessment timepoint.

If the patient did not receive the QoL Documents OR they have not been returned within 7 days the site will telephone the patient and request the QoL assessment to be completed and returned to the site in the reply paid envelope.

If the patient is unable or unwilling to complete and return the QoL assessment for any reason the trial coordinator will request permission to ask the QoL questions over the telephone.

If the patient is unwilling or unable to answer the QoL assessment for any reason this will be documented.


All attempts to contact the patient to complete the QoL assessments will be documented. The QOL Assessment Checklist Report Form (CRF) will be completed at each specified time point to collect information on the completion of QoL assessments and will document the method of follow-up and any reasons for missing/incomplete QoL data.

8.7.3 Non-English Speaking Patients If a patient cannot speak or read English, the questionnaire will be requested from the EORTC in the appropriate language, for use by the patient. If the questionnaire is not available in the patient’s language, this will be documented on the QOL Assessment Checklist Report Form (CRF) form. 9.0 PATIENT PREFERENCES STUDY Patients who consent to participate in the TROG 11.03 PLUNG study, and who are able to read and write in English, will also be invited to participate in a Patient Preferences Study. This will require the patient to undergo an additional informed consent process and sign a consent form specific to the Patient Preferences Study (see Appendix 13).

9.1 Objectives

The objective of the Patient Preferences Study is to determine how much improvement in QoL and symptom palliation would be necessary to make the inconvenience due to the longer duration of radiotherapy of C-HDPRT worthwhile, relative to the HDPRT.

9.2 Research Plan

A discrete choice experiment (DCE) methodology will be employed. In a DCE, respondents exercise their preferences by making repeated trade-offs and choices across a series of hypothetical scenarios whose attributes change in a systematic way (according to an underlying experimental design). In this case, the attributes will be the common symptoms (cough, dyspnoea, haemoptysis and chest pain), the main side-effect (dysphagia), aspects reflecting the inconvenience of attending for radiotherapy, and the duration of radiotherapy. Realistic levels of these attributes will be combined in a systematic fashion to develop a series of hypothetical scenarios. Experimental design principles will be used to select the optimal sample of scenarios with the appropriate statistical properties to allow the most efficient quantification of the effect of the attributes on the probability of choosing one alternative over another. Data collection will be performed by trained interviewers using a computer assisted telephone interview (CATI). The Hunter Valley Research Foundation (HVRF) will be contracted to undertake the interviews. The HVRF is an independent, not-for-profit research organisation which has undertaking research since 1956. The CATI program was developed in-house by the HVRF staff. Patient Preferences Survey booklets will be distributed to the Trial Sites by the Trial Coordinating Centre. Consenting patients will be given a copy of this booklet by the research staff at the trial site (for example the medical officer or data manager) at the time of consent. The patient will provide a telephone number, which will be conveyed to staff at the HVRF, who will then arrange a suitable time for a telephone interview. The telephone interview will take place after consent is obtained and before the patient starts treatment. The patient preferences data will be collected via CATI. During the telephone interview, the patient will use the patient preferences booklet which will contain a series of hypothetical treatment scenarios, presented in pairs. The telephone interviewer will ask the respondent to identify


which option s/he prefers for each pair of scenarios. The patient is encouraged to read through the questionnaire and give some thought to their preferences prior to the telephone interview. It is anticipated that it will take participants between 20-40 minutes to complete the questionnaire. The patient is able to ask the interviewer any questions they may have regarding the survey. All patient answers will be recorded in the computer database designed by the HVRF. All patient answers will be kept strictly confidential. Only researchers involved in the study will see the answers and the name and personal details of the patient will not be included. Contact details for the Hunter Valley Research Foundation are: Address: PO Box 322 Newcastle NSW 2300 T: 02 4969 4566 F: 02 4961 4981 Email: [email protected] 10.0 BIOLOGICAL SUBSTUDY

In consenting patients, 20 ml peripheral blood will be collected for serum, plasma, white blood cells and PAXgene® Blood DNA. Tissue sample collection will include one haematoxylin and eosin stained slide, a formalin-fixed paraffin-embedded tissue block or tissue core and a tissue sample preserved in a PAXgene® (PreAnalytiX) tissue container. Specimens will be preserved at the Princess Alexandra Hospital Tumour Tissue Bank. A panel of putative biomarkers will be developed in the exploratory arm of this study by profiling the glyoproteome and exosomal proteome and miRNA using 20 selected patient samples. Two cohorts of 10 samples will be used, (1) patients who demonstrate progression within 3 months and (2) patients who have not progressed within 3 months. Glycoproteomics Serum samples (50 ul) will be screened using high throughput lectin magnetic bead array coupled to tandem mass spectrometry (HT-LeMBA-MS) as established in the laboratory of CI- Hill. A panel of 15 lectins will be used in this discovery study. The required infrastructure, including sample preparation liquid handler system, liquid chromatography-tandem mass spectrometer and associated software are already established at the University Queensland Diamantina Institute at the PAH campus. Exosome analysis Exosomes will be prepared from 250 ul of serum sample using ExoQuick exosome precipitation reagent. (1)Proteomics: Precipitated exosomes will be solubilised in phosphate-buffered saline supplemented with 0.5% SDS and the protein concentration will be determined using BCA protein assay (Pierce). 10 microgram of each sample will be separated on SDS-PAGE gel and slices will be digested with trypsin using our established high throughput in-gel digest protocol. Peptides will be analysed by LC-MS/MS and protein identities will be inferred through database searching. (2).MicroRNA (miRNA): short RNA will be prepared using miRNAeasy kit (Qiagen), and profiled using RT2 cancer miRNA PCR array (SABiosciences) with SYBR green RT PCR master mix. Real time PCR instrument is available at UQ Diamantina Institute.



11.0 ASSESSMENT OF EFFICACY

11.1 Endpoint Definitions

11.1.1 Primary Endpoints

The primary endpoints are: the change in the Intrathoracic Symptom Burden Index from baseline to 6 weeks

from the end of treatment; and

the changes in each of the four symptoms, dyspnoea, cough, haemoptysis and chest pain from baseline to 6 weeks from the end of treatment.

The six week time-point has been chosen for the primary endpoints because this is when the maximal symptomatic benefit is expected.

Definition: Intrathoracic Symptom Burden Index

Intrathoracic Symptom Burden Index is defined, for the purposes of this study, as the average of 4 components based on items from EORTC QLQ LC13: dyspnoea (3 items, Q33-Q35), cough (Q31), haemoptysis (Q32) and chest pain (Q40). The scores for the three dyspnoea items will be averaged. The average of this figure and the scores for cough, haemoptysis and chest pain will be standardised to a 0 to 100 scale to give the Intrathoracic Symptom Burden Index (ISBI).

ISBI = 100*{[(Q33+Q34+Q35)/3 + Q31 + Q32 + Q40 ]/4 - 1}/3

where, Q33 is the score (1, 2, 3 or 4) for question Q33, etc.

For assessing change in dyspnoea, the average of the three dyspnoea item scores at baseline and at each subsequent time-point will be calculated.

11.1.2 Secondary Endpoints

11.1.2.1 Profiles of change from baseline of the mean of Intrathoracic Symptom Burden Index (defined in 11.1.1) and of each of the four component symptoms, involving each time-points 6 weeks and 3, 6, 9, 12 and 24 months after end of treatment, calculated for each arm. 11.1.2.2 Area under curve (AUC) of dysphagia (LC13, Q37) during treatment, derived from changes from baseline at weeks 3, 2 and 1 prior to the end of treatment and at the end of treatment, using the trapezoidal method. For Arm A, for which treatment lasts only 2.5 weeks, dysphagia at 3 weeks prior to treatment will be assigned the baseline value.

11.1.2.3 Thoracic symptom response and response duration.

a. Thoracic symptom response will be defined as a reduction of the Intrathoracic Symptom Burden Index by at least 10 units (on the standardised 0-100 scale) from baseline

b. Thoracic symptom progression following response will be defined as a symptom burden of 10 units or higher above the nadir

Assessment of Intrathoracic Symptom Burden Index and hence thoracic symptom response and thoracic symptom progression, will be undertaken at each follow-up time point (3, 6, 9, 12 months after end of treatment).

c. Thoracic symptom response duration is defined for patients who respond and is the time from response to progression.


11.1.2.4 Physician’s rating of cough, dyspnoea, haemoptysis and chest pain, summed into a symptom index, as for the Intrathoracic Symptom Burden Index. 11.1.2.5 Physician’s rating of performance status (Karnofsky) and QOL (Spitzer). 11.1.2.6 The area under the curve (AUC) of the overall QOL measure (QLQ-C30, Q29, Q30, using standard scoring as per the EORTC QLQ-C30 Scoring Manual68), from baseline to the return to baseline value or to last follow-up, using the trapezoidal method. 11.1.2.7 Profiles of all standard domains (multi-item scales) and single-item scales from the EORTC QLQ-C30 and QLQ-LC13 (as per standard EORTC scoring for these questionnaires59, 68), will be similarly assessed. 11.1.2.8 Toxicity measured by NCIC CAE v 3.0. After a comparison of both Version 3.0 and version 4.0, version 3.0 was selected as the most applicable criterion to this group of patients and their potential toxicities, as defined in the protocol. 11.1.2.9 Tumour response The initial assessment of tumour response will be determined 6 weeks after all protocol treatment has been completed, whether or not all of the planned treatment was received. The RECIST (Response Evaluation Criteria in Solid Tumours) criteria must be used for assessment of tumour response. (Appendix 9) 11.1.2.10 Progression-free survival, measured from the date of randomisation to the date of objective documentation of tumour progression or death from any cause. 11.1.2.11 Overall survival, measured from the date of randomisation to the date of death from any cause.

11.2 Assessment Tools

11.2.1 Quality of Life (QOL) Questionnaire

11.2.1.1 EORTC QLQ-C30 and EORTC QLQ-LC13 The EORTC QLQ-C30 and the QLQ-LC13 are copyrighted quality of life assessment instruments and will be used under agreement with the EORTC for the purposes of this trial. Refer to Appendix 8 for a copy of the questionnaires. The EORTC QLQ-C30 assesses global health status and QOL Functional (physical; role; emotional; cognitive; social) and symptom scales (fatigue; nausea and vomiting; pain; dyspnoea; insomnia; appetite loss; constipation; diarrhoea; financial difficulties).(58) The EORTC QLQ-LC13 is a lung cancer specific module designed to be used with the EORTC QLQ-C30 core quality of life questionnaire(59). The EORTC-LC 13 assesses coughing, breathing pain/discomfort; tingling/numbness/pins and needles; swallowing, hair loss, mouth/throat (dry, sore, sticky saliva). Both of these questionnaires will be completed in accordance with the time points specified in Section 8. Information regarding the standardised administration of this questionnaire for all trial participants is provided in Appendix 8.


11.2.1.2 Spitzer Index The Spitzer Index, designed to be used by physicians, provides a succinct quantitative measurement of quality of life(60). Refer to Appendix 4 for a copy of the questionnaire. The Spitzer Index will be used in this trial in accordance with the time-points specified in Section 8. 11.2.1.3 Karnofsky Performance Scale The Karnofsky Performance Scale Index allows patients to be classified as to their functional impairment(61). This can be used to compare effectiveness of different therapies and to assess the prognosis in individual patients. The lower the Karnofsky score, the worse the survival for most serious illnesses. Refer to Appendix 5 for a copy of the questionnaire. The Karnofsky Performance Scale index will be used in this trial in accordance with the time-points specified in Section 8. 12.0 ADVERSE EVENT SCORING and REPORTING It is important that Adverse Events (AEs) are monitored in the interest of patient safety. The investigator at each trial site is responsible for assessing and reporting AEs as part of routine clinical care and data collection. A subset of AEs will be classified as ‘serious’ and will require expedited reporting.

12.1 Definitions

12.1.1 Adverse Event (AE)

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product (or any other protocol specified intervention including Radiation Therapy, surgery or use of a device) and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign, symptom or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product (or associated with the use of any other protocol specified intervention including radiation therapy, surgery or use of a device). AEs include: ‘Adverse Drug Reactions’, i.e.

A reaction, in contrast to an event, is characterised by the fact that a causal relationship between the drug and the occurrence is suspected.

For unapproved medicines: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase ‘responses to a medicinal product’ means that a causal relationship between a medicinal product and an adverse event is at least reasonably possible, i.e. the relationship cannot be ruled out.

Regarding marketed medical products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function.


12.1.2 Unexpected Adverse Events (UAE) An Unexpected Adverse Event is an AE for which the nature or severity of the event is not consistent with the information in the relevant source documents (or with the applicable side effect risk profile for radiation therapy, surgery or use of a device). UAEs include: ‘Unexpected Adverse Drug Reactions’, i.e.

The nature and severity of the ADR is not consistent with the information in the Investigators Brochure for an unapproved investigational product, or the product information/package insert/summary of product characteristics for an approved product.

12.1.3 Serious Adverse Event (SAE)

Adverse events and adverse drug reactions are considered ‘serious’ if they threaten life or function. SAEs include: ‘Serious Adverse Drug Reactions’ During clinical investigations, adverse events may occur which, if suspected to be medicinal product related (‘adverse drug reactions’), might be significant enough to lead to important changes in the way the medicinal product is developed (e.g. change in dose, population, monitoring, consent). This is particularly true for reactions which in their most severe form threaten life or function. Due to the significant information they provide, Serious Adverse Events (including Serious Adverse Drug Reactions) require expedited reporting. SAEs are defined as any adverse event or adverse drug reaction which:

Results in death (i.e. fatal/grade 5 CTC AE)

Is life-threatening (i.e. grade 4 CTC AE)

Requires inpatient hospitalisation or prolongation of existing hospitalisation*

Results in persistent or significant disability/incapacity; or

Is a congenital anomaly/birth defect

Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the participant was immediately at risk of death at the time of event; it does not refer to an event which hypothetically might have caused death if it were more severe. *An event that results in hospitalisation or prolongs an existing hospitalisation will not be considered a serious adverse event if the only reason for the hospitalisation or prolongation was:

administration of chemotherapy

administration of trial procedures

placement of a permanent intravenous catheter

hospice placement for terminal care

pre-trial scheduled elective surgery

out-patient hospitalisation for procedures such as:

o Elective day surgery

o Convenience purposes (e.g. transportation difficulties)

o Planned admission as part of supportive care for insertion of PEG tube or naso-gastric tube for commencement of enteral feeding (i.e. did not occur following urgent admission as a result of weight loss or other patient medical events)


12.1.4 Attribution of Cause of an Adverse Event

Attribution of cause requires at least a reasonable possibility of a causal relationship between the event and the use of a pharmaceutical product (or any other protocol specified intervention including radiation therapy, surgery or use of a device), i.e. the relationship cannot be ruled out. One or more of the following categories should be attributed as the cause of an event:

Pharmaceutical product (an SAE which is drug related is considered a Serious Adverse Drug Reaction)

Radiation Therapy

Medical Device

Surgery

Unrelated to trial treatment (i.e. progressive disease, concurrent medication, concurrent disorder or other

All protocol specified interventions (including pharmaceutical products, radiation therapy, surgery or use of a device) administered prior to the date of the event must be attributed a degree of causality from one of the following codes:

Unrelated

Unlikely to be related

Possibly related

Probably related

Definitely related

12.2 Reporting

12.2.1 Adverse Event Reporting

12.2.1.1 Trial Sites/Investigators All adverse events (including those that are non-serious or expected) which occur whilst the participant is enrolled on the trial must be reported in the patients’ medical records and recorded on the relevant CRF. The Common Terminology Criteria for Adverse Events (CTCAE version 3.0 – see appendices) must be used to grade the severity of an event. 12.2.1.2 Trial Coordinating Centre (TCC) Data from the CRF will be entered onto the trial database at the Trial Coordinating Centre and accessed when required by TROG. Regular analyses of cumulative AE data should occur at the TCC. If significant safety issues are identified from analyses the TCC must inform the TSC, the Therapeutic Goods Administration (TGA), other investigators and responsible HRECs.


12.2.2 Serious Adverse Event Reporting

12.2.2.1 Trial Sites/Investigators All SAEs that occur from the time a participant is registered/randomised on the Trial to within 30 days of the final protocol-specified treatment, intervention or procedure are required to be reported to the Trial Coordinating Centre (TCC) and the TROG Central Operations Office (TCOO) whether or not considered related to the treatment under investigation. The Principal Investigator (PI) must:

Determine whether an AE is ‘Serious’ (refer to criteria at 10.1.3)

For SAEs, the PI must then ascertain the suspected cause

The attribution to the SAE must be recorded in the patients’ medical records and reported on the SAE form.

The PI must then determine whether the SAE (or Serious Adverse Drug Reaction) is expected or unexpected.

Both expected and unexpected Serious Adverse Events and Serious Adverse Drug Reactions must be recorded in the patients’ medical records and reported to the TCC and TCOO

Unexpected Serious Adverse Drug Reactions that are fatal or life threatening must be further reported to the TGA according to section 10.4.3 below. SAEs must be reported by completing the TROG SAE form and FAXING it to the following:

Fax To: Fax Number:

Trial Coordinating Centre (TCC) +61 (0)7 3176 1929

TROG Central Operations Office (TCOO) +61 (0)2 4014 3902

SAE forms are required at the following points:

Initial Report

Within one working day/24 hours of discovery or notification of the event. If the reporting of an SAE is delayed by more than 24 hours, an explanation must be provided in the comments section of the SAE form.

Incomplete Reports*

If all details are not available at the time of the initial report, a completed report must be sent within the next 10 days.

Updated Report

If the event is not resolved (or is ‘on-going’) at the time of the initial report, the ‘UPDATE: Outcome of Event’ section’ of the SAE Form must be completed and the form submitted to the TCC and the TCOO as soon as the event is resolved (with or without sequelae) or if death has occurred.

*The Investigator is ultimately responsible for reporting the SAE and must sign the SAE report(s). Should this Investigator not be available to sign the initial SAE form within the 24 hour period, a comment to this effect must be written on the form and the form faxed without signature to the TCC and TCOO. The investigator must sign the SAE form as soon as possible and re-fax to the TCC and the TCOO.


The Investigator at the Trial Site is responsible for determining the local SAE reporting requirements of the responsible HREC and subsequently notifying the HREC of SAEs as required. All Serious ADRs (expected and unexpected) are required to be reported to the TCC and the TCOO according to section 10.2.2 above. 12.2.2.2 Trial Coordinating Centre (TCC) The TCC will ensure all SAEs are forwarded for immediate clinical review by a qualified independent reviewer to ensure any safety issues and subsequent actions are identified as soon as possible. If the Trial Chairperson and the Principal Investigator consider that the SAE is drug related and unexpected (i.e. an Unexpected Serious ADR), it must be reported to the Experimental Drugs Section, Drug Safety Evaluation Branch of the Therapeutic Goods Administration (TGA) by the Trial Coordinating Centre (on behalf of TROG), using the ADRAC ‘blue card’, within 7 calendar days of the occurrence of the event if fatal or life threatening or 15 days if not. A follow up report must be provided to the TGA within a further 8 calendar days. The Trial Chairperson must send a letter explaining the event to all trial investigators as soon as possible. In general, all expected and non-serious ADRs recorded during the course of the trial are to be amalgamated into a single report which is sent to the TGA (by the TCC) at the conclusion of the trial. There may however be situations where a non-serious or an expected ADR may require individual, rapid reporting to the TGA. Appropriate scientific judgement should be applied for each situation. Examples of the type of information that may require reporting are;

a) For an ‘expected’ serious ADR, an increase in the rate of occurrence which is judged to be clinically important

b) A significant hazard to the patient population such as lack of efficacy with a medicinal product used in treating life threatening disease.

c) A major safety finding from a newly completed animal study (such as carcinogenicity).

The Investigator at the Trial Site is responsible for reporting Serious ADRs to the responsible HREC according to local requirements.

12.2.3 Other situations requiring expedited reporting

12.2.3.1 Overdoses Overdoses (drug or radiation) must be reported to the TCC and TCOO (see section 10.4.2) if the event(s) associated with the overdose meet the SAE definitions in section 10.1.4. If no serious adverse events are experienced the overdose must be reported in the patients’ medical record and transcribed onto the relevant trial CRF. 12.2.3.2 New Cancers The development of new cancers at any time during the trial must be reported in the patients’ medical record and transcribed onto the relevant trial CRF. If any events associated with the new cancer meet the SAE definitions listed at section 10.1.4 above, then they should also be reported to the TCC and TCOO (see section 10.4.2).


12.3 New Zealand reporting requirements

New Zealand Investigators (i.e. Trial Sites) must follow the reporting requirements outlined above for reporting of Adverse Events, Serious Adverse Events and Serious Adverse Drug Reactions The TCC (on behalf of TROG) must report all Unexpected Serious ADRs to the Centre for Adverse Reactions Monitoring (CARM), as soon as possible, by using the Adverse Reaction Reporting Card. An electronic version of this card is available at: http://www.medsafe.govt.nz/downloads/ADRMedicines.doc 13.0 TREATMENT DISCONTINUATION, PARTICIPANT WITHDRAWAL/TRANSFER A Trial Participant may discontinue trial treatment for any of the following reasons:

a) Disease progression as defined in section 11.1.2 b) Unacceptable toxicity c) Intercurrent illness which prevents further treatment d) Withdrawal of consent for treatment by participant e) Any alterations in the participant’s condition which justifies the discontinuation of

treatment in the investigator’s opinion

Discontinuation of treatment does not necessarily indicate withdrawal from the trial. The distinction between discontinuation of treatment and withdrawal from the trial is shown by the definitions in the following subsections.

13.1 Protocol Treatment Discontinuation

A participant would be considered to have discontinued treatment where trial related treatment is ceased according to the reason(s) outlined above. The participant may however still agree to further follow-up assessments as scheduled in section 8.0, including quality of life assessments. The participants’ discontinuation of treatment must be documented in the medical records (i.e. source documents) and transcribed onto the relevant CRF.

13.2 Withdrawal from Trial

Trial Participants have the option to completely withdraw from the trial at any time without giving a reason. Total withdrawal would occur in the circumstance that the participant decides to completely withdraw from all treatment aspects of the trial, and does not agree to any further scheduled follow up assessments. The participants’ total withdrawal must be documented in the medical records and transcribed onto the relevant CRF. No further information will be collected from this patient for the purpose of this trial.

http://www.medsafe.govt.nz/downloads/ADRMedicines.doc


13.3 Patient Transfers

Every effort should be made for a trial participant moving from the area to continue their treatment and/or follow-up at another participating Trial Site and for this Trial Site to take over responsibility for the participant. Until the new Trial Site formally agrees (in writing) to take over responsibility and provides evidence of ethics approval, the patient remains the responsibility of the original Trial Site. Source documentation will remain at the original Trial Site. One copy of the participant’s CRFs must be sent to the new Trial Site and one copy will remain at the original Trial Site. 14.0 STATISTICAL CONSIDERATIONS

14.1 Trial Design

This is an open label, phase III, comparative, multi-centre randomised clinical trial whose primary objective is to determine whether C-HDPRT is better that HDPRT in terms of relief of the intrathoracic symptoms, dyspnoea, cough, haemoptysis and chest pain. Secondary objectives include comparisons of a number of other QoL and toxicity endpoints, as well as comparison of progression-free survival and overall survival.

14.2 Treatment Assignment

Patients will be randomised in the ratio of 1:1 between the two arms, HDPRT and C-HDPRT. Allocation to treatment arms will be stratified by tumour stage (III, IV), tumour histology (adenocarcinoma, SCC, other), major chest symptoms (presence or absence of each of dyspnoea, cough, haemoptysis and chest pain) and treating Institution, using the minimisation technique (with a random component). The next treatment assignment will not be known to any person prior to randomisation; and cancellation of any randomisation will not be permitted.

14.3 Statistical Methods

Baseline characteristics by treatment arm will be summarised in frequency tables and by the use of descriptive statistics for quantitative variables. Summary tables will be prepared giving numbers of patients by treatment arm and by randomisation irregularities, treatment compliance, eligibility infringements, and losses to follow-up (as per CONSORT guidelines). All patients with a valid baseline QOL assessment and at least one follow-up QOL questionnaire will be included in the analysis. The baseline questionnaire will be considered valid if filled out and dated by the patient in the two weeks prior to the starting date of trial treatment. Reasons for missing baseline and follow-up QOL questionnaires will be assessed. A table of QoL compliance rates (QoL assessments completed as a percentage of expected) by arm will be reported. Analysis of the primary objective The primary objective will be assessed initially by comparing the mean change in Intrathoracic Symptom Burden Index from baseline to 6 weeks from end of treatment between arms, adjusting for baseline index. The analysis will be performed using a linear regression model. If there is a significant difference in change of Intrathoracic Symptom Burden Index between arms, each of the four symptoms included in the index (dyspnoea, cough, haemoptysis, chest pain) will be assessed separately to assess the relative relief obtained by the symptoms. For each symptom, only patients who present with the symptom will be included


in the analysis. The mean change from baseline of cough, haemoptysis and chest pain by arm, conditional on baseline score, will be analysed using the Cochran test for ordinal data from data in a 2 x 6 contingency table (arm by change in score). Analysis of dyspnoea will be similar. The Hochberg method will be used to assess the four endpoints while maintaining the overall type I error at 5% or less.

Analysis of secondary objectives Profiles of various QoL measures (including Intrathoracic Symptom Burden Index, major chest symptoms, overall QoL summary score and domains of QoL) by arm of the mean of the measure by time will be analysed via a linear mixed models approach. Various linear contrasts will be analysed including comparisons of arms at specific time-points and area under curve. A Hochberg adjustment (62) will be used to adjust for multiple hypothesis testing across domains and time points. Comparison by arm of dysphagia will be performed in terms of the area under the curve (AUC) summary measure over the period of treatment (4 weeks prior to the end of treatment). Dysphagia will be measured at 4 weeks (baseline), 3, 2 and 1 week prior to and at end of treatment. As the RT-only arm is only 2.5 weeks in duration it will be assumed that dysphagia is at the same level as at baseline. A linear mixed model will be used from which change from baseline dysphagia AUC adjusting for baseline dysphagia will be compared. Thoracic symptom response rates (section 11.1.2.3) will be compared between arms using the Barnard test for comparing proportions. Thoracic symptom response duration will be assessed using time-to-event methods (following). Death will be a censoring event. The Kaplan-Meier method will be used to estimate curves for overall survival, progression-free survival; logrank tests and Cox regression will be used to compare arms and adjust for prognostic factors. All times to events will be measured from the date of randomisation. A close-out date will be determined at the time of final analysis as the earliest date of last contact of all patients alive and not lost to follow-up. All follow-up beyond this date will be ignored for the purposes of analysis in order to minimize bias arising from the differential reporting of follow-up for patients who experience an event. Ninety-five percent confidence intervals (95% CI) for differences between arms of all important endpoints will be calculated, and P-values will be two-sided.

14.4 Sample Size Calculation and Expected Duration

The sample size has been based on the ability to show a mean difference between arms of 10 points (on 0-100 standardised scale) in the Intrathoracic Symptom Burden Index. Although data on this index is not available differences of this size are generally agreed to be clinically important in similar measures. (64) The pre-treatment standard deviation (SD) within arms of each of four measures is likely to be approximately 30.(65) The SD of the

change from baseline at 6 weeks is given by the formula, )1(2SD where is the

correlation coefficient between the baseline and 6 week score. Using a correlation of 0.8(36) the relevant SD for sample size calculation is 19.0. This approach corresponds to an effect size of about 0.5 which also corresponds to a symptom score difference that has been recommended as representing a minimal important difference (MID).(66)


The total sample size, for 1:1 allocation of patients to arms, is that which enables a mean difference between arms in change from baseline QoL score of 10 percentage points to be detected with a power of 80% using a two-sided test. Allowing for 10% of patients being not-fully-evaluable, the target total sample size will be 130 patients. Patients are expected to be accrued at the rate of about 15 patients per year in the first 6 months, 30 in the next 6 months and 45 patients per year thereafter, and all patients will be followed until 14 months after registration of the last patient to allow for collection of the 12-month post-treatment QoL data. Thus,

The target sample size is 130 patients, expected to be accrued over 41 months and followed for a further 14 months, which will provide 80% power to detect a difference between arms of 10 percentage points in change from baseline of Intrathoracic Symptom Burden Index at 6 months from end of treatment, using a two-sided test at the alpha = 0.05 level of significance.

The planned sample size and trial duration will enable a hazard ratio between arms for OS of 0.59 (corresponding to survival rates of 50% versus 66% at the median survival for the control arm) (12) to be detected with 80% power. Sample size for the preferences substudy is dependent on the number of attributes and levels in the DCE. The former cannot be calculated until the latter are determined, which will occur in the first year of the project. In order to make the preference substudy feasible within this study, the number of attributes and levels will be constrained such that the study sample size for the main study is sufficient to estimate the preference models. The statistical model for DCE preference data is the random parameter logit model. (67) These models will be estimated using maximum simulated likelihood, implemented in NLOGIT software. Biological substudy Biostatistical analysis will be performed to derive signatures of serum glycoproteins and exosomes that correlate with therapeutic response. A panel of putative biomarkers will be selected for verification in future experiments. 14.5 Analysis Plan Regular progress reports will be done six-monthly for the TMC and TROG meetings. It is planned to monitor toxicity, via the Independent Data Monitoring Committee (IDMC), after each year of accrual, to ensure that toxicity does not exceed reasonable levels in either arm. No interim assessment of the primary objective will be performed; and no futility analysis will be performed. Approximately six months before the target sample size is expected to be reached, a reassessment of the sample size will be undertaken (i.e., checking the main assumption upon which this was made, namely the standard deviation in each arm of the change from baseline of the QoL statistic at 6 weeks from end of treatment.)


Event Purpose Trigger Expected Date Months from SOA

Expected accrual

SOA Jul 2012 0 0

IDMC Toxicity 45 patients Jan 2014 18 45

IDMC Toxicity 90 patients Jan 2015 30 90

IDMC Check sample size assumptions

Approx. 6 months before EOA

Jun 2015 35 110

EOA 130 patients Dec 2015 41 130

EOF 14 months after EOA Feb 2017 55 130

FA Assess all objectives Apr 2017 57 130

Legend: SOA = start of accrual; EOA = end of accrual; EOF = end of follow-up; IDMC =Independent Data Monitoring Committee; FA = final analysis.

Table 12: Summary of Main Events and Analyses.

14.6 Early Termination Criteria

Early termination, or modification, of the trial will be considered in the event of any of the following:

Inadequate recruitment: less than 20 patients per year once a consistent accrual rate has been established and all trial sites have been opened.

Unacceptable toxicity (as assessed by the IDMC);

Evidence becoming available, during the accrual phase of the trial, which clearly demonstrates that it is unethical to randomise patients to one or both of the trial arms.

15.0 DATA MANAGEMENT AND QUALITY ASSURANCE

15.1 Trial Site Data Management

CRFs will be supplied by the Trial Coordinating Centre. Trial Site Coordinators and Principal Investigators (and/or Sub-investigators) at participating Trial Sites must transcribe source data from the source documents onto the CRFs as soon as they are collected. Completed original CRFs should be returned to the TROG Central Trial Database System (CTDS) via the TROG Teleform Faxline: (0) 2 4014 3618. This fax number is to be used for fax submission of all CRFs (except for eligibility and randomisation which are completed on-line via web registration). A ‘Forms Due Schedule’ will be provided, and CRFs should be returned at the times specified and a copy of each CRF should be kept at the Trial Site. Trial Participants are to be identified by initials, trial registration/randomisation number and Trial Site. All CRFs should be completed in black ink and never in pencil. All requested information must be entered on the CRFs. If an item is not available or is not applicable, this fact should be indicated; do not leave a space blank. A correction should be made by striking through the incorrect entry with a single line and by entering the correct information adjacent to it. The correction must be initialed and dated by an adequately qualified and authorised member of the research support team at the Trial Site.


15.2 Source Documents

The Trial Site will prepare source documentation for QA reviews. Source data, including medical histories, radiological imaging, laboratory tests, chemotherapy and radiotherapy treatment records and verification films and portal images, must be retained for 15 years after completion of the trial and be available for checking or clarification of queries by the TCC if required, in accordance with ICH GCP Guidelines.

15.3 Quality Assurance Reviews

15.3.1 Regulatory Reviews

Regulatory reviews will be undertaken by the Trial Coordinating Centre who will require a copy of the ethics approval letter for each site participating in this trial. Copies of contracts, agreements and other regulatory documents required for the trial will also be collected by the Trial Coordinating Centre.

15.3.2 Eligibility Reviews

Reviews of eligibility compliance will be performed for all cases prior to registration on the trial by the trial coordinating centre.

15.3.3 QoL Questionnaire compliance reviews

Reviews of completion rates of forms will be undertaken regularly by the Data Monitoring Committee (DMC) to ensure that the expected 90% return rate is achieved at each scheduled time point for completion. The DMC will also review reasons for non-completion (as reported on the QOL Assessment Checklist Report Form [Q5]). A 90% return rate is also expected for the QOL Assessment Checklist Report Form.

15.3.4 Radiotherapy Treatment Delivery

15.3.4.1 Credentialing Centre credentialing is not required for this trial as part of the QA program.

15.3.4.2 Technical Individual Case Reviews (ICRs)

The first three cases from each centre will be reviewed at the end of radiotherapy treatment. Please refer to section 7.1.9 for further information on the radiotherapy quality assurance requirements for this trial.

15.3.5 Chemotherapy Reviews

For each participant, a checklist of information required for chemotherapy review (i.e. treatment charts/’flow sheets’) which clearly demonstrate the prescription and administration of chemotherapy drugs will be provided by the TROG QA Office. Review material will be required at the end of treatment. CRFs and the copies of chemotherapy records will be reviewed for each participant to assess and verify compliance with the protocol. Audits will focus on delivered dose, method of administration, treatment timing and dose modifications. Copies of laboratory results will be required to verify dose delays/modifications.


15.4 Site Visits and Monitoring

The QA program for this trial will be amended if required (at the discretion of the Trial Management Committee) to include site visits. 15.5 Data Monitoring Committee An independent DMC will be convened with the purpose of:

Assessing quality issues related to RT and systemic therapy

Assessing the conduct and progress of the trial – accrual, non-eligibility, treatment toxicity and serious adverse events.

Monitoring return and completion rates of QoL questionnaires This committee will make appropriate recommendations to the TROG Scientific Committee. 16.0 ETHICAL CONSIDERATIONS

16.1 Ethical Principles and Regulatory Compliance

The trial will be conducted according to the following regulations and guidelines:

Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) annotated with TGA comments (Australia, July 2000)

The Australian Code for Responsible Conduct of Research (August 2007)

Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects (last amended by the World Medical Association, 2008)

Interim Good Clinical Research Practice Guidelines (New Zealand, August 1998),

National Statement on Ethical Conduct in Human Research, (Australia, 2007)

Guidelines on Ethics in Health Research (NZ, 2005), and

Current TROG Policy Statements This Protocol, including the Participant information Sheet and Consent Form (PIC) must be approved by the responsible HREC before enrolment of trial participants.

16.2 Adherence to Protocol

Except for an emergency situation in which proper care for the protection, safety and well being of the trial participant requires that an alternative treatment be used, the trial shall be conducted exactly as described in the approved protocol.

16.3 Informed Consent

The Principal Investigator is responsible for ensuring that written Informed Consent is obtained from trial participants before participating in the TROG 11.03 PLUNG trial and the Patient Preferences Study. Template Participant Information Sheet and Consent Forms (PICs) are provided in Appendices 11 and 14 The Principal Investigator must insert site specific information into both templates and have them approved by the TCC prior to submitting the PICs to the responsible HREC for ethics approval. If the patient does not speak English, the informed consent process may be carried out in the presence of an interpreter however the patient would need to complete the QoL forms in their own language by themselves (i.e. without an interpreter). Refer to section 8.6.3.


16.4 Confidentiality

The trial will be conducted in accordance with applicable Privacy Acts and Regulations. All information regarding trial participants must be treated in strict confidence. Data, which identify any trial participant, must not be revealed to anyone not directly involved in the trial or the clinical care of that participant. An exception is where the trial participant has provided written consent for his/her records to be included in source document verification. In this instance, the records may be inspected by (a) a representative of TROG for the purposes of source document verification or quality audit as stipulated in the ICH GCP Guidelines, or (b) a representative of a government regulatory authority for the purposes of official inspection. Records must be made available for inspection on the understanding that all information relating to trial participants will be treated in strict professional confidence. 17.0 INSURANCE AND COMPENSATION TROG endorses the principles of the Medicines Australia Guidelines for Compensation for Injury Resulting from Participation in a Company Sponsored Trial and the Research Medicines Industry equivalent in New Zealand. To provide protection for trial participants involved in TROG Clinical Trials, TROG maintains a clinical trials insurance policy. The policy does not include patients recruited from North America. 18.0 PUBLICATION AND PRESENTATION POLICY

18.1 Reporting of Results

The Trial Management Committee will be responsible for decisions regarding presentations and publications arising from this trial according to the TROG Authorship, Publication and Spokesmanship Guidelines. Access to data during the trial will be limited to the TCC, the TCOO as required for QA reviews, the TMC, the DMC and appropriate regulatory bodies. The primary analysis of trial results for publication will be performed by the TMC statistician. The primary trial results will be published by TROG. Acknowledgement of TROG is required in all publications, abstracts and presentations. Publications and abstracts must be presented to the TMC for review and approved prior to submission. In addition, publications must be reviewed by the TROG Publications Committee prior to submission.

18.2 Trial Registry

The TCOO is responsible for registering all TROG trials with an appropriate clinical trials registry prior to the accrual of the first participant. All TROG trials are registered at www.clinicaltrials.gov and Australian and New Zealand Clinical Trials Registry (ANZCTR) www.anzctr.org.au.

http://www.actr.org.au/


19.0 REFERENCES

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http://www.canceraustralia.gov.au/about-cancer/cancer-information/cancer-in-Australia


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Appendix 1

Staging

TNM staging system for lung cancer (7th edition)

Primary tumor (T)

T1 Tumor ≤3 cm diameter, surrounded by lung or visceral pleura, without invasion more proximal than lobar bronchus

T1a Tumor ≤2 cm in diameter

T1b Tumor >2 cm but ≤3 cm in diameter

T2 Tumor >3 cm but ≤7 cm, or tumor with any of the following features:

Involves main bronchus, ≥2 cm distal to carina

Invades visceral pleura

Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T2a Tumor >3 cm but ≤5 cm

T2b Tumor >5 cm but ≤7 cm

T3 Tumor >7 cm or any of the following:

Directly invades any of the following: chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, main bronchus <2 cm from carina (without involvement of carina)

Atelectasis or obstructive pneumonitis of the entire lung

Separate tumor nodules in the same lobe

T4 Tumor of any size that invades the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or with separate tumor nodules in a different ipsilateral lobe

Regional lymph nodes (N)

N0 No regional lymph node metastases

N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension

N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).


Appendix 1

Staging Continued

Distant metastasis (M)

M0 No distant metastasis

M1 Distant metastasis

M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural or pericardial effusion

M1b Distant metastasis

Stage groupings

Stage IA T1a-T1b N0 M0

Stage IB T2a N0 M0

Stage IIA T1a,T1b,T2a N1 M0

T2b N0 M0

Stage IIB T2b N1 M0

T3 N0 M0

Stage IIIA

T1a,T1b,T2a,T2b N2 M0

T3 N1,N2 M0

T4 N0,N1 M0

Stage IIIB

T4 N2 M0

Any T N3 M0

Stage IV Any T Any N M1a or M1b


Appendix 2

ECOG Performance Status Criteria

Grade ECOG

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

As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.


Appendix 3

Cockcroft-Gault Formula for Calculating Creatinine Clearance

Women:

Creatinine clearance in mL/min = 1x (140-age [yr] ) x body wt [kg]

Serum creatinine [umol/L]

or

Creatinine clearance in mL/min = 0.85 x (140-age [yr] ) x body wt [kg]

72 x serum creatinine [mg/dL]

Men:

Creatinine clearance in mL/min = 1.23 x (140-age [yr] ) x body wt [kg]

serum creatinine [umol/L]

or

Creatinine clearance in mL/min = 1x (140-age [yr] ) x body wt [kg]

72 x Serum creatinine [mg/dL]

As published in Nephron Journals: Cockcroft DW, Gault MH: Prediction of Creatinine Clearance from Serum Creatinine. Nephron 1976;16:31-41 (DOI: 10.1159/000180580)


Appendix 4 Physician rated Spitzer Index

Score each heading 2, 1 or 0 according to your most recent assessment of the subject. Activity During the last week the subject

Has been working or studying full-time, or nearly so, in usual occupation; or managing own household; or participating in unpaid or voluntary activities, whether retired or not

Has been working or studying in usual occupation or managing own household or participating in unpaid or voluntary activities; but requiring major assistance or a significant reduction in hours worked or a sheltered situation or was on sick leave

Has not been working or studying in any capacity and not managing own household Daily Living During the last week, the subject

Has been self-reliant in eating, washing, toileting and dressing; using public transportation or driving own car

Has been requiring assistance (another person or special equipment) for daily activities and transport but performing light tasks

Has not been managing personal care nor light tasks and/or not leaving own home or institution at all

Health During the last week, the subject

Has been appearing to feel well or reporting feeling “great” most of the time

Has been lacking energy or not feeling entirely “up to par” more than just occasionally

Has been feeling very ill or “lousy”, seeming weak and washed out most of the time or was unconscious

Support During the last week

The subject has been having good relationships with others and receiving strong support from at least one family member and/or friend

Support received or perceived has been limited from family and/or friends by the subject’s condition

Support from family and friends occurred infrequently or only when absolutely necessary or subject was unconscious


Appendix 4 Physician rated Spitzer Index Continued

Outlook During the last week, the subject

Has usually been appearing calm and positive in outlook, accepting and in control of personal circumstances, including surroundings

Has sometimes been troubled because not fully in control of personal circumstances or has been having periods of obvious anxiety or depression

Has been seriously confused or very frightened or consistently anxious and depressed or unconscious

Quality of Life Index Total How confident are you that your scoring of the preceding dimensions is accurate?

Please circle the appropriate category. Absolutely Very Quite Not Very Very Not at all Confident Confident Confident Confident Doubtful Confident 1 2 3 4 5 6 Reference:

<http://www.ncbi.nlm.nih.gov/pubmed/7309824?ordinalpos=26&itool=EntrezSystem 2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocS um> WO, Dobson AJ, Hall J, Chesterman E, Levi J, Shepherd R, Battista RN, Catchlove BR. Measuring the quality of life of cancer patients: a concise QL-index (QLI) for use by physicians. J Chronic Dis 1981, 34:585-97


Appendix 5 Karnofsky Performance Scale Index

The Karnofsky Performance Scale Index allows patients to be classified as to their functional impairment. This can be used to compare effectiveness of different therapies and to assess the prognosis in individual patients. The lower the Karnofsky score, the worse the survival for most serious illnesses.

Able to carry on normal activity and to work; no special care needed.

100 Normal no complaints; no evidence of disease.

90 Able to carry on normal activity; minor signs or symptoms of disease.

80 Normal activity with effort; some signs or symptoms of disease.

Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed.

70 Cares for self; unable to carry on normal activity or to do active work.

60 Requires occasional assistance, but is able to care for most of his personal needs.

50 Requires considerable assistance and frequent medical care.

Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly.

40 Disabled; requires special care and assistance.

30 Severely disabled; hospital admission is indicated although death not imminent.

20 Very sick; hospital admission necessary; active supportive treatment necessary.

10 Moribund; fatal processes progressing rapidly

0 Dead

References:

Crooks, V, Waller S, et al. The use of the Karnofsky Performance Scale in determining outcomes and risk in geriatric outpatients. J Gerontol. 1991; 46: M139-M144.

de Haan R, Aaronson A, et al. Measuring quality of life in stroke. Stroke. 1993; 24:320 – 327.

Hollen PJ, Gralla RJ, et al. Measurement of quality of life in patients with lung cancer in multicentre trials of new therapies. Cancer. 1994; 73:2087 – 2098.

O’Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J Med. 1991; 155:384 – 387.

Oxford Textbook of Palliative Medicine, Oxford University Press. 1993; 109.

Schag CC, Heinrich RL, Ganz PA, Karnofsky performance status revisited: Reliability, validity, and guidelines. J Clin Oncology. 1984; 2:187 – 193.


Appendix 6

Schedule of Assessments

Pre-Registration Pre-Treatment Week 1 Week 2 Week 3 Week 4

Inclusion/ exclusion criteria

Medical history √

Current height √ √

Current weight √ √ √ √ √ √

Informed Consent √

Physical examination √ √ √ √ √ √

ECOG performance √ √ √ √ √ √

Histology/pathology report √

Peripheral blood and tumour sample for banking and biological studies

√

CT (chest,abdomen+/-brain) √

FDG-PET √

Haematology screening √ √ √ √* √* √*

Biochemistry screening √ √ √ √* √* √*

Pregnancy test √

Creatinine Clearance √** √** √**

Respiratory function tests √

General

Quality of life EORTC QLQ-C30, EORTC LC-13 Physician rated Spitzer index

√ √ √ √ √ √

Karnofsky performance status √

Calculate BSA √

Concomitant Medication √ √

AE/SAE √ √ √ √

Toxicity assessment (NCIC CTCAE v 3.0) √ √ √ √ √


* Only required For those patients receiving chemotherapy (i.e. Arm B). It is recommended that bloods be taken on day 1 of each week

** If there is an increase in serum creatinine above baseline or a decrease in body weight in excess of 10% of baseline a creatinine clearance estimation is required (see section 7.2.13)

*These assessments will also be completed at the time of progression

Patient preferences questionnaire √

Radiotherapy

Radiotherapy 36Gy/12f arm 1 √ √ √

Radiotherapy 40 Gy/20f arm 2 √ √ √ √

Chemotherapy

Arm A- No chemotherapy

Arm B- IV cisplatin 20mg/m2

IV vinerolbine 25mg/m

2

√ √ √ √

√ √ √

Forms/ QA collection

CRF completion + submission √ √ √ √ √

QA checklist completion √ √

Follow-up: Time from Completion of Protocol Treatment

2 weeks 6 weeks 3 months 6 months and every 3 months

thereafter until progression

Quality of Life (QLQ-C30, QLQ-LC13) Physician rated Spitzer index

√ √ √ √*

Physical examination √ √ √ √*

Toxicity assessment (NCIC CTCAE v 3.0) √ √ √ √*

Concomitant medication √ √ √ √

CT chest/upper abdomen+/- PET √ √ √ ( if clinically indicated)*


Appendix 7

CTCAE (Common Terminology Criteria for Adverse Events, V3.0)

Available at:

http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf As published by the U.S Department of Health and Human Services, National Institutes of

Health National Cancer Institute: August 2006

http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf


Appendix 8

Quality of Life Questionnaires

EORTC QLQ-C30 (version 3) - (Kaasa et al, 1995; Hjermstad et al, 1995)



EORTC QLQ - LC13


Appendix 9

Recist Response Criteria Eisenhauer E, Therasee P, Bigaerts J: New response evaluation criteria in solid

tumours: REVISED RECIST guideline (version 1.1) European Journal of Cancer 2009: 45

(2): 225-310

Evaluation of target lesions

Complete Response (CR) Disappearance of all target lesions. Any

pathological lymph nodes (whether target or

non-target) must have reduction in short axis

to <10mm

Partial Response (PR) At least a 30% decrease in the sum of

diameters of target lesions, taking as

reference the baseline sum diameters.

Progressive Disease (PD) At least a 20% increase in the sum of

diameters of target lesions, taking as

reference the smallest sum on study (this

includes the baseline sum if that is the

smallest on study). In addition to the relative

increase of 20%, the sum must also

demonstrate an absolute increase of at least

5mm. (Note: the appearance of one or more

new lesions is also considered progression)

Stable Disease (SD) Neither sufficient shrinkage to qualify for PR

nor sufficient increase to qualify for PD,

taking as reference the smallest sum

diameters while on study.


Appendix 10

Radiotherapy

1. Pictorial Representations of Target Volumes

The Gross Tumour Volume (GTV) is defined as the primary tumour and clinically involved loco-regional lymph nodes seen either on planning CT scan (>1cm short axis diameter) or pre-treatment FDG PET scanning.

The Clinical Target Volume (CTV) is defined as the GTV plus 0.5cm in all directions. Elective treatment of the mediastinum and supraclavicular fossae will not be performed.

The Planning Target Volume (PTV) is defined as the CTV plus 1.0cm in all directions

GTV CTV

PTV


GTV CTV

PTV


Appendix 11

Participant Information Sheet and Consent Form

PARTICIPANT INFORMATION SHEET

TROG 11.03: A RANDOMISED PHASE III TRIAL OF HIGH DOSE PALLIATIVE

RADIOTHERAPY (HDPRT) VERSUS CONCURRENT CHEMOTHERAPY +

HDPRT (C-HDPRT) IN PATIENTS WITH GOOD PERFORMANCE STATUS, LOCALLY ADVANCED/SMALL VOLUME METASTATIC NSCLC NOT

SUITABLE FOR RADICAL CHEMO-RADIOTHERAPY (“P_LUNG GP)”

Coordinated by the Trans Tasman Radiation Oncology Group (TROG) in collaboration with the Australian Lung Cancer Trials Group

INTERPRETER FOR MEDICAL INFORMATION

NZ Sites must include this section

English I wish to have an interpreter Yes

Maori E Hiahia ana ahau ki tetahi kaiwhakamaori/kaiwhaka pakeha korero

Ae

Samoan Oute mana’o ia iai se fa’amatala upu Ioe

Tongan Oku ou fiema’u ha fakatonulea Io

Cook Island Ka inangaro au I tetai tangata uri reo Ae

Niuean Fai Manako au ke fakaaoga e taha tagata fakahokohoko kupu E

1. Invitation

You are invited to take part in a cancer research trial, also known as a clinical trial or ‘study’.

Before you decide if you would like to take part in the study you need to understand why the

research is being done and what it would involve for you. Please take time to read the

following information carefully and to decide if you wish to take part in the study. Talk to

others about the study if you wish and feel free to ask us if there is anything that is not clear

or if you would like more information.

You can use family [insert /whanau for New Zealand sites] support or a friend to help ask

questions and understand the study.

2. Why have I been invited?

You have been invited to participate in this study because you have been diagnosed with

non-small cell lung cancer (NSCLC).


There are a number of different treatment options for NSCLC. The actual treatment given to

a patient with NSCLC depends on their general health and the extent of their tumour (also

termed their tumour stage).

As your doctor will have explained, your disease cannot be treated with surgery or with a

long (six weeks or longer) course of radiation therapy combined with chemotherapy. This

may be because of the size of your tumour or because you have other medical conditions

that may be affected by a long course of radiation therapy. Your doctor will have also

explained that a short (less than six weeks) course of radiotherapy is a common treatment

approach when surgery or a long (more than six weeks) course of radiotherapy and

chemotherapy is not possible. The aim of a short course of radiotherapy is to relieve

symptoms (such as cough, coughing up blood, shortness of breath or chest pain) and to

control the cancer for as long as possible.

Chemotherapy is often given with long (six weeks or longer) courses of radiation therapy in

patients with cancer. A number of studies have shown that giving chemotherapy and

radiotherapy together gives better results than giving the treatments by themselves, however

it is not known if giving chemotherapy with a short course of radiotherapy will have similar

benefits.

This study is trying to determine whether the addition of chemotherapy to a short (less than

six weeks) course of radiotherapy is a better treatment approach in patients with NSCLC

who cannot undergo surgery or long course radiotherapy and chemotherapy.

Your participation in this study is voluntary and you can withdraw at any time.

A total of 130 patients will participate in this study.

3. What is the purpose of this clinical research study?

The purpose of this study is to investigate whether adding chemotherapy to a short (less

than six weeks) course of radiotherapy results in a greater improvement in symptoms and

overall wellbeing (quality of life) compared with using a short course of radiotherapy alone in

patients with NSCLC who cannot be treated with surgery or a long (six weeks or longer)

course of radiotherapy and chemotherapy.


4. What does this study involve?

This is a “randomised” study. Sometimes we don’t know which way of treating patients is

best. We therefore need to compare different treatments amongst groups of patients to find

out which treatment is better. In a randomised study a computer program will choose which

group you are allocated to. Neither you nor your doctor will be able to decide which

treatment you will receive.

In this study, you will be allocated by chance to either short course radiotherapy or short

course radiotherapy and chemotherapy. You have an equal chance of getting the standard

short course of radiotherapy (12 treatments over 21/2 weeks) or the experimental arm of

radiotherapy (20 treatments over 4 weeks) and chemotherapy.

If you decide to take part in the study:

You will be asked to sign the consent form and your doctor will arrange for any

additional study specific procedures to be conducted prior to confirming your inclusion in

the study.

These procedures include:

(1) Questions about your medical history

(2) A physical examination

(3) Blood samples for routine blood tests including a pregnancy test (if applicable)

(4) Breathing tests to assess how well your lungs work

You will also be asked to complete two questionnaires, called Quality of Life

Questionnaires, to assess how you are feeling before treatment is started. This will take

about 15 minutes.

If you do not speak or read English we will try to obtain a questionnaire in your

language. If the Quality of Life forms are not available in your language you may still

participate in the trial if you wish.

You will be allocated to one of two arms. You have an equal chance of being allocated

to either arm.

If you are allocated to standard treatment, you will be required to attend for radiation

treatment planning and then for 12 radiation treatments, given once a day, five days a

week for 2½ weeks. There will be no chemotherapy.

If you are allocated to the experimental arm, you will be required to attend for radiation

treatment planning and then for 20 radiation treatment, given once a day, five days a

week for four weeks. In addition, chemotherapy will be given once a week, each week

during the four week course of radiotherapy. On days 1, 8 and 22 of radiotherapy you


will receive 2 intravenous (into the vein) chemotherapy drugs, cisplatin and vinerolbine.

On day 15 of the radiotherapy you will receive only 1 intravenous drug, cisplatin.

Both the cisplatin and vinerolbine chemotherapy are administered intravenously. This

involves having a sterile plastic needle inserted into a vein on the hand or forearm which

is attached to plastic tubing. A nurse will slowly inject the chemotherapy. This will take

approximately 1-2 hours.

During treatment

You will be asked to fill out the Quality of Life questionnaire weekly.

You will also meet with your doctor weekly and s/he will ask you questions about

any side effects you may be experiencing due to the treatment.

After treatment is completed, you will see your doctor at 2 weeks post treatment, 6

weeks post treatment and then at 3 monthly intervals

These visits will take approximately 30 minutes. You may be required to have

Xrays or CT scans of your chest or a PET scan and routine blood tests requiring

approximately 10mls(2 teaspoons) of blood to assess your blood cell counts, liver

and kidney function. You will also be required to fill out a Quality of Life

questionnaire, which may take up to 15minues to complete.

You are welcome to bring your family [insert /whanau for New Zealand sites] to all

appointments.

5. What will be required of me if I decide to participate in this study?

If you decide to participate in this study it will be your responsibility to tell your doctor about

any other medical conditions you have, any other medications you are taking (including non-

prescription medications, vitamins or herbal remedies) and/or if you have experienced any

previous reactions to a medicine. You must also inform your doctor of any changes to these

medications during your participation in the study.

6. What are the possible risks from participating in this study?

All medical procedures involve some risk. In addition, there may be risks associated with this

study that are presently unknown or unforeseeable. In spite of all reasonable precautions,

you might develop medical complications from participating in this study. The known risks of

this study are:


If you are allocated to standard radiotherapy, the risks are:

Fatigue

Mild redness and tanning of the skin in the area receiving radiation (temporary)

Discomfort on swallowing due to inflammation of the oeosphagus (gullet) (temporary)

Shortness of breath and cough due to inflammation of the lung developing weeks to

months after treatment (“pneumonitis”). Usually this is temporary and improves without

the need for treatment. Uncommonly it requires treatment with steroid medication (eg

cortisone). Very rarely it can be fatal.

If you are allocated to radiotherapy and chemotherapy, the risks are:

Fatigue

Mild redness and tanning of the skin in the area receiving radiation (temporary)

Discomfort on swallowing due to inflammation of the oeosphagus (gullet) (temporary)

Shortness of breath and cough due to inflammation of the lung developing weeks to

months after treatment (“pneumonitis”). Usually this is temporary and improves without

the need for treatment. Uncommonly it requires treatment with steroid medication (eg

cortisone). Very rarely it can be fatal.

Loss of appetite, nausea, vomiting

During the week following your chemotherapy your blood cell counts may drop. This

can affect you in three ways:

(1) A lowering of your white blood cells (the cells that fight bacteria) means that you are

prone to infections. If you feel unwell or have a temperature at this time you need to

notify your Oncologist immediately or go straight to the Emergency Department of the

Hospital to be treated with antibiotics.

(2) A lowering of your platelet count (the cells responsible for blood clotting) which may

cause bruising or bleeding. You should notify your doctor if you notice any of these

symptoms.

(3) A lowering of your red blood cells (the cells that carry oxygen around your body) may

cause anaemia. If this occurs you may feel tired and possibly short of breath. It may be

necessary to treat this with a blood transfusion.

Constipation

Irritation of the veins into which the medicine has been injected.

Soreness of the mouth


Conception, Pregnancy and Breast feeding

It is important that women participating in this study are not pregnant and do not become

pregnant during the study as radiotherapy and chemotherapy may damage an unborn baby.

Women should not breastfeed whilst participating in this study as radiotherapy and

chemotherapy may affect the baby.

If you are a woman of childbearing age and there is any possibility that you are pregnant, the

researchers will need to perform a urine pregnancy test before you start in the study.

Both male and female participants are strongly advised to use effective contraception during

the course of the study and for a period of six months after completion of the study. You

should discuss methods of effective contraception with your doctor. If you or your partner

become pregnant whilst participating in the study you should advise your treating doctor

immediately. He/she will withdraw you from the study and advise on further medical attention

should this be necessary. You must not continue in the study if you become pregnant.

Chemotherapy may cause temporary or permanent sterility. Please discuss this with your

doctor if you have any concerns about future fertility.

7. What are the possible side effects of the treatment I will be receiving if I participate

in this study?

Side effects experienced from radiotherapy and chemotherapy and their severity can vary

from person to person. Your doctor will discuss these side effects with you, you will be

regularly assessed and medication may be prescribed or your treatment modified to control

any side effects you may experience. Your family doctor will also be kept informed.

Radiation Treatment

Radiation treatment will be administered according to study instructions. Side effects

experienced during radiation treatment are usually temporary and should gradually get

better once the treatment has finished.

Likely to be experienced by more than 50% of

participants(more than 50 in 100 participants)

May be experienced by 5-50% (5-50 in 100) of

participants:

Likely to be experienced by less than 5% of participants

Fatigue Nausea Shortness of breath and cough

(“pneumonitis”)

Skin redness and tanning

Discomfort on swallowing

Chemotherapy

Chemotherapy will be administered according to study instructions. A small plastic tube

(called a cannula) will be inserted into a vein in your hand or arm. A plastic tube will connect


this cannula with a plastic bag containing the chemotherapy medication. The chemotherapy

medication will slowly move down this plastic tube into your vein. It will take between 1 to 2

hours for one of the chemotherapy medicines to be given and around 30 minutes for the

second chemotherapy medicine to be given. You will be sitting comfortably in a chair while

this occurs.

You may experience some side effects associated with this treatment, as outlined below.

Risks associated with Cisplatin

Likely to be experienced by more than 50% (more than

50 in 100) of participants

May be experienced by 5-50% of participants:


Fatigue Numbness or Tingling in the hands and feet

Fall in blood counts (red blood cells, white blood

Cells and platelets) with A risk of anaemia, infection

Or bleeding

Changes in kidney function as Seen by blood tests

(including loss of potassium Or magnesium that may

Require treatment

Nausea and vomiting Allergic reactions which may include rash,

Fever and itching.

Ringing in the ears or decreased ability to

Hear normal conversation

Risks associated with Vinorelbine

Likely to be experienced by more than 50% (more than 50 in 100) of participants

May be experienced by 5-50% of participants:


Fatigue Constipation Numbness or Tingling in the hands and feet

Fall in blood counts (red blood cells, white blood cells, and platelets) with a

risk of Anaemia, infection or bleeding

Redness and discomfort at

The site of injection

Muscle, joint aches

Sore mouth Hair loss Loss of appetite, Nausea, vomiting

Side effects will be minimized with anti-nausea medication and steroid medication and will

be monitored by your doctor with blood tests and physical examination if appropriate.

If you are concerned about these or any other symptoms contact Dr (insert name).


8. What are the Possible Benefits from participating in this study?

If your assigned treatment program proves to be more beneficial than the other treatment

program, then you may benefit medically from your involvement in this research study.

However benefit is not guaranteed. Other people with non-small cell lung cancer may

benefit in the future from knowledge gained from this research study.

9. What are the alternative treatments or procedures (if I don’t want to take part in the

study)?

If you do not wish to take part in the study, you will be offered the standard treatment given

in the hospital where you are being treated.

10. What happens when the study finishes?

You will continue to be followed by your doctor with regular Xrays as is normally the case for

patients who are monitored following treatment for lung cancer. If your cancer recurs, it will

be treated by the most appropriate standard methods.

11. Can the study be stopped early?

Sometimes we get new information about the treatment being studied. If the information is

related to one of the following reasons the researchers may decide to make adjustments to

the study or, in rare cases, stop the study early in order to protect you;

reports of unacceptable side effects

the data being collected shows to the researchers that the treatment being used in

this study is not being effective in the treatment of your disease/condition.

the data being collected shows to the researchers that the treatment being used in

this study is working and does not need further investigation

a decision may be made by the Human Research Ethics Committee to stop the

study.

your doctor may decide, at any time, that it is in your best interest to remove you from

this study.

If the study is adjusted for any of the above reasons, your doctor will tell you and discuss

whether you should continue in the study. If you decide not to carry on, your doctor will make

arrangements for your care to continue. If you decide to continue in the study he may ask

you to sign an updated consent form.

If the study is stopped early your doctor will explain the reasons and arrange for your care to

continue.


12. What will happen if I don’t want to carry on with the study?

You can completely withdraw from the study at any time, without having to give a reason.

Please notify a member of the research team if you decide to withdraw.

Alternatively, you have the option of withdrawing from treatment only. This means that you

would still have the option of attending study related follow up assessment visits and

receiving continuation of care with your study doctor. This would be entirely your choice.

Withdrawal from the study in any form WILL NOT jeopardise the treatment that you receive

now or in the future, your relationship with the staff caring for you or your ongoing care at

this hospital.

13. What happens if I suffer an injury or complications as a result of the study?

This study is sponsored and coordinated by the Trans Tasman Radiation Oncology Group

(TROG), a not-for-profit research group involving many cancer researchers in Australia and

New Zealand, as well as internationally.

If you suffer any injuries or complications that may be as a result of your participation in this

study, you should immediately contact your doctor, who will assist you in arranging

appropriate medical treatment.

In the unlikely event of an injury caused by your participation in this study, compensation

may be payable to you. TROG maintains a clinical trials insurance policy. Please ask your

doctor if you would like more information on this policy.

14. Will my family doctor be involved?

It is desirable that your family doctor be advised of your decision to participate in this study.

By signing the Consent Form you agree to your family doctor being notified of your decision

to participate in this study.

15. How will my confidentiality be protected?

Any identifiable information that is collected about you in connection with this study will

remain confidential and will be disclosed only with your permission, or except as required by

law.

If you join the study, some information in your medical records and the data collected for the

study will be looked at by authorised persons as delegated by TROG - the group organising

the study. They may also be looked at by representatives of regulatory authorities.

Your doctor may also need to obtain some of your health information from other health

service providers such as another hospital, pathology laboratory, radiotherapy centre, your

family doctor or a medical specialist.


16. Collection of Tissue Samples for Research Purposes

Tissue that was removed at your biopsy was used to make microscope slides that were

examined by a Pathologist to make the diagnosis of non-small cell lung cancer. The slides

are prepared from small tissue blocks. We would like permission to obtain some of the

excess tissue stored from your biopsy for research. We would also like permission to take a

blood specimen for research.

The purpose of the research is to learn more about non-small cell lung cancer, especially to

determine if there are “markers” that predict how a patient will response to radiotherapy and

chemotherapy.

If you agree, only tissue that has already been removed and stored in your local pathology

departments will be used. You will not need to have further biopsies taken. Researchers will

use special techniques to examine the tissue under a microscope. They will also remove

some tissue from the microscope slides and examine it in test tubes. These studies will

include studying the DNA of your abnormal lung cells.

If you agree, you will also have a blood test. This is just like many routine blood tests and a

couple of teaspoons of blood will be taken before you start treatment.

Research studies on your tissue and blood specimen will not be carried out immediately.

They may not be carried out for months or years. Results of these research studies will not

influence your treatment on study. The results will not routinely be given to you or your

doctor.

Tissue and blood samples collected for this research project will be processed and stored at

the Princess Alexandra Hospital in Brisbane. The samples may be kept until they are used

up. To protect your privacy, any information on your tissue sample slides that may identify

you will be removed and replaced with a unique identification number only. In the case of

your blood sample, your initials, date of birth and a unique identification number will be

placed on the storage vessel only. This number will be used in the discussion and

presentation of results and no information that would allow you to be identified will be

revealed.

Your tissue and blood samples may be used for genetic research. The researchers will

ONLY look for changes relevant to your lung cancer and the treatment being tested. The

researchers will NOT be looking at your DNA to see if you have inherited a risk for other

diseases. The researchers will NOT be looking at your DNA to detect information such as

non-paternity, non-maternity or information that may influence access to

insurance/employment.


Future research

Your information and tissue samples may be helpful for future research into non-small cell

lung cancer in Australia or overseas. Future researchers may wish to look at information and

tissue samples from this project. Any future research will only be done after approval by a

research ethics committee and all your information and samples will remain de-identified.

Participation in the tissue testing/genetic testing arm of this study is optional. If you agree to

participate in this optional tissue testing/genetic testing arm of the study, please sign the

separate Tissue Sample Consent Form attached.

17. What will happen with the results of the study?

It may be a number of years before the results of this research are available. When the

results are available they will be published as ‘journal articles’ in medical journals. Your

identity will not be revealed in these journal articles. Please ask your doctor if you want to

know more about this.

18. Will participation cost me anything, and will I be paid?

Participation in this study will not result in any additional expense for you. You will not be

paid for your participation in this study.

19. Further information and contact details

Who do I contact for advice?

Please read this information sheet carefully. Feel free to ask for clarification on any aspect of

the study that you do not understand. Your doctor will answer any questions you may have.

You may also wish to discuss the study with a relative or friend or your local health worker.

Feel free to do this. Do not sign the consent form if you have not received satisfactory

answers to your questions and/or you have doubts about participating in this study.

If you want to know more about this project or if you have any medical problems during this

project (for example, any side effects), you can contact one of following people:

Principle Investigator: Dr Margot Lehman

Telephone: 07 3176 2111

Co-Investigator: Assoc Professor Michael Michael

Telephone: 03 9656 111

Trial Coordinator: Cassie Freriechs

Telephone: [07 3176 8292


Who do I contact for advice after hours?

If you have any medical problems during this project (for example, any side effects) and

need to speak to someone urgently after hours please contact:

Name

Contact Number 1

Contact Number 2

Who should I contact if I have concerns about the conduct of the study?

If you have any complaints about any aspect of the study, the way it is being conducted or

any questions about your rights as a research participant, then you may contact:

Ethics Coordinator: [Insert Name]

Telephone: [Insert number]

Or

Patient Advocate


You will need to tell the Ethics Coordinator or the Patient Advocate the name of the researcher given on page 15 of this Participant Information and Consent Form.

Thank you for taking the time to consider being part of this study.

If you wish to take part in this study, please sign the attached consent form.

This information sheet is for you to keep.


CONSENT FORM

TROG 11.03: A RANDOMISED PHASE III TRIAL OF HIGH DOSE PALLIATIVE RADIOTHERAPY

(HDPRT) VERSUS CONCURRENT CHEMOTHERAPY + HDPRT (C-HDPRT) IN PATIENTS

WITH GOOD PERFORMANCE STATUS, LOCALLY ADVANCED / SMALL VOLUME METASTATIC

NSCLC NOT SUITABLE FOR RADICAL CHEMO-RADIOTHERAPY (P_LUNG GP)

By signing this consent form:

1. I confirm that I have read, or have had read to me in a language I understand, the

Participant Information Sheet ([insert version number and date]) for the above study.

I have had the opportunity to consider the information, ask questions and have had

these answered satisfactorily.

2. I understand that my participation is voluntary and that I am free to withdraw at any

time without giving any reason, without my medical care or legal rights being

affected.

3. I understand that relevant sections of my medical notes and data collected during the

study may be looked at by individuals from TROG or from regulatory authorities

where it is relevant to my taking part in this research. I give permission for these

individuals to have access to my records.

4. I give permission for doctors, other health professionals, hospitals or laboratories

outside this hospital to release information concerning my disease and treatment that

is needed for this study. I understand that such information will remain confidential.

5. I agree to my family doctor being informed of my participation in the study

6. I agree to take part in the above study.

7). I understand that I will be given a signed copy of this document to keep.


Signatures

Patients (or Guardians) Name Signature Date

Witness Name (where required) Signature Date

Declaration by the Interpreter

I hereby declare that I was present and interpreted for the informed consent process with the patient.

Name of Interpreter (where required) Signature Date

Declaration by the Investigator

I hereby declare that I have discussed the purpose, procedures and risks of this research study with the patient.

Name of Principal Investigator/Delegate Signature Date

You are participating on a TROG Cancer Research Trial. If you wish to learn more

about this trial or TROG please visit www.trog.com.au



CONSENT FORM FOR TISSUE SAMPLE STORAGE AND USE (To be included only if required)

TROG 11.03 - A RANDOMISED PHASE III TRIAL OF HIGH DOSE PALLIATIVE RADIOTHERAPY




By signing this consent form I give permission for the following:

1. The storage and use of blood and tissue samples taken from me to be used in further

research as described in the Participant Information Sheet

2. The use of my tissue samples for genetic testing as outlined in the Participant Information

Sheet

Signatures













REVOCATION OF CONSENT FORM

TROG 11.03 - A RANDOMISED PHASE III TRIAL OF HIGH DOSE PALLIATIVE RADIOTHERAPY




By signing this consent form I give notice to;

(Please initial one)

Discontinue treatment from the study named above.

I do not wish to receive any further treatment prescribed by this study however I

would like to continue to attend study related follow-up visits with my study doctor.

Totally withdraw my consent to participate in the study named above. I do not wish

to receive any further treatment or attend study related follow up assessments. I

understand that such withdrawal WILL NOT jeopardise the treatment that I receive

now or in the future, my relationship with the staff caring for me or my ongoing care

at this hospital..


Declaration by the Interpreter I hereby declare that I was present and interpreted for the trial participants’ withdrawal of consent.






Appendix 12

Collection of blood and tissue specimens

1.0 Blood

Peripheral blood will be collected for serum; plasma; white blood cells and PAXgene® Blood DNA. Requirements Specimen collection 1 x 10mL EDTA whole blood (Plasma) 1 x 8mL SST/Clot (Serum) 1 x Paxgene DNA Blood Tube Sample collection All specimen tubes should be transported at room temperature (RT) before processing (to prevent red cell lysis before centrifugation), however, if travel at longer distance from pick up point to lab, keep the specimen bag with tubes inside on top of ice in an esky during transportation to prevent extreme temperature fluctuation; after centrifugation, keep spun EDTA and SST/Clot blood on ice before aliquoting. Serum and Plasma should be extracted and frozen within 2 hours of collection All bloods should be processed within 48 hours of collection. Cell viability decreases rapidly after 48 hours, resulting in poor cell structure in slide preparations and degradations of proteins and nucleic acids. Use cryovials for storage purpose (see Table below) Label all tubes with TROG study number; patient study number; initials; Date of Birth; Date of sample collection (pre-printed labels will be provided).

Blood Components Storage Number of Cryovials

Serum (SST/Clot tube) -800C 6 vials, 500ul per vial

Plasma (EDTA tube) -800C 8 vials, 500ul per vial

Blood Pellet (BP) (EDTA tube)

-800C 3 vials (minimum 2 vials)

Paxgene DNA Blood -800C 1 tube

SST/CLOT Serum Processing Protocol 1. Centrifuge blood at 2500 rpm at 40C for 15 mins

2. Aliquot 500ul each into 6 cryovials and store in the freezer box.

EDTA Blood Processing Protocol We aim to aliquot ~10mL of EDTA blood into:

6 aliquots of plasma stored at -800C

3 aliquots of blood pellet (minimum 2 aliquots) stored at -800C for future DNA extraction


Collection of EDTA - Plasma: 1. Centrifuge the EDTA vacutainer at 2500 rpm for 15 mins at 40C (This step can be

performed with the 1st step of procedure 3.1 for serum collection). NB: Ensure that the rotor is balanced

2. After centrifugation, take the EDTA tubes to the Biosafety Cabinet and wipe the top of tube with alcohol wipe.

3. Remove about 3 – 5 mL of plasma (take care not to disturb the buffy coat), then transfer the plasma into one clean 15mL Falcon centrifuge tube. Retain the EDTA tube for Blood Pellet collection in procedure 3.2.2

4. Centrifuge the 15mL Falcon tubes at 4000rpm for 10 min at 40C

NB: The purpose of double spinning the plasma is to remove all cellular contaminants (to achieve cell-free plasma). It is important not to disturb the buffy coat after first spin and any pellet after second spin.

5. Aliquot 500ul of plasma into 6 labeled cryovials and store the aliquots in the freezer box.

Collection of Blood Pellet (BP):

1. Bring the Red Cell Lysis buffer to room temperature. The lysis buffer contains Ammonium Chloride.

2. Dilute the 10x stock Lysis buffer solution to 1x working solution with MQ water in a 50mL tube.

3. Transfer the remaining blood from the EDTA Tube A from procedure 3.2.1 into a clean 50 mL centrifuge tube

4. Fill the 50mL centrifuge tube with 1x Red cell lysis buffer up to the 50mL mark and mix with Pasteur pipette then incubate it in 370C water bath for 5 mins.

5. Centrifuge at 300g for 5 mins at RT

6. Discard the supernatant and wash the BP with Hank’s Balanced Salt solution

7. Repeat the centrifugation and washing of the cell pellet for a total of 2 washes

8. Discard the supernatant and resuspend with ~ 1.5mL Hank’s Balanced Salt solution to dissociate the cell pellet, then aliquot 500ul BP each into 3 labeled cryovials and store in the freezer box.

White Blood Processing Protocol Collection of WBC(PBMC) using Ficoll-Paque PLUS:

1. Wipe the top of Tube B with alcohol wipe before opening the lid. 2. Transfer the blood from Tube B into a 50ml tube.

3. Into the 50ml tube, add RPMI-1640 culture medium (without serum) at the ratio Blood:RPMI medium = 1:1 and mix by pipetting up and down with a Pasteur pipette

4. Invert the Ficoll-Paque PLUS bottle several times to ensure thorough mixing. Snap-off the polypropylene cap (when open a new bottle). Insert the sterile syringe needle through the septum. Inject air from the syringe to equalize pressure. Invert the bottle and withdraw 10mL of Ficoll-Paque PLUS.

5. Add Ficoll-Paque PLUS into a clean 50ml BD Falcon tube.


6. Carefully layer the diluted blood sample onto the Ficoll-Paque PLUS using a clean Pasteur pipette

NB: Layering of the blood needs to be done slowly (put the tip of the Pasteur pipette against the side of the tube) to prevent mixing of Ficoll-Paque PLUS and the diluted blood sample

7. Centrifuge at 1600 rpm for 30 minutes at room temperature WITHOUT BRAKE

8. After centrifugation, carefully remove the 50ml tube from the centrifuge (Do not disturb the lymphocyte layer) and bring it to the Biosafety Cabinet. Draw off the clear upper layer (plasma) using a clean Pasteur pipette and discard into a waste bottle, leaving the PBMC layer (a white layer of cells between the upper layer and the Ficoll underneath) undisturbed at the interface.

Procedure for washing the WBCs(PBMC) to remove platelet and Ficoll:

1. Using a clean Pasteur pipette transfer the PBMC layer into a clean 15ml centrifuge tube. It is critical to remove all of the interface but a minimum amount of Ficoll-Paque PLUS and supernatant.

NB: Removing excess Ficoll-Paque PLUS causes granulocyte contamination; removing excess supernatant results in contamination by platelets and plasma proteins.

2. Top the 15ml centrifuge tube with RPMI-1640 medium to 12ml mark and mix the cells by gentle inversion.

3. Centrifuge at 1800 rpm for 10 mins at RT (BRAKE CAN BE USED HERE)

4. Remove the supernatant and discard it

5. Wash the cells 2 times using the RPMI-1640 and then remove the supernatant

6. The PBMC should now be re-suspended in cold freezing medium (3ml) and aliquoted into 3 X 1ml cryovial and stored at -80 deg C.

PAXgene DNA Blood Tube

1. Label the PAXgene DNA Blood Tube with the pre-printed label. 2. Store the PAXgene DNA Blood Tube in the appropriate box in -800C freezer.

Samples will be stored at each participating institution and shipped to the Diamantina Institute, after every 5 patient samples are collected.

Samples will be packed in biohazard bags in Styrofoam boxes and shipped on dry ice to:

Attention: Michelle Hill

Research Fellow The University of Queensland Diamantina Institute

Level 4, R-Wing Princess Alexandra Hospital

Ipswich Road, Woolloongabba Qld 4102 Tel: 61 (07) 3176 7456 Fax: 61 (07) 3176 5946

Email: [email protected]



2.0 Tissue

Tissue Collection Protocol

1 TROG study number, patient study number and initials are to be labelled on all containers used for collection.

2 Upon collection, the pathologist will examine the specimen by palpating it and determine whether the size of the tumour is large enough (i.e. tumour ≥ 10mm) for sampling for the bank.

3 The amount of tissue collected is determined by the size of the tumour (N.B. collect no more than ¼ of the tumour, and stay clear of the resection margins). The registrar will ink and dissect the specimen. Ask the registrar to cut a slice of normal tissue away from the tumour + a slice of tumour tissue (change new blade for each one) and leave them in separate clean Petri dishes for further dissection.

4 Collect normal tissue first to avoid contamination to the instruments with tumour tissues.

5 Work as quickly as possible and process the samples as follows

6 Collection and processing of normal tissue:

Cut a sample of normal tissue, then dissect it into ~5 mm3 cubes, place one cube per one sterile pre-labelled (e.g. 0001N) tube (clear cap), recap the tube tightly and snap freeze in liquid nitrogen

Place one cube in OCT medium in an aluminium foil boat or cryomold and snap freeze it in liquid nitrogen

Place one cube in 10% NBF (Neutral Buffered Formalin) to process for paraffin sectioning

Place once cube in RNA later, then freeze at -80 deg C

7 Collection and processing of tumour tissue:

Cut a sample of tumour tissue, then dissect it into ~5 mm3 cubes, place one cube per one sterile pre-labelled (e.g. 0001T) tube (clear cap), recap the tube tightly and snap freeze in liquid nitrogen



Place one or more (if enough) cubes (maximum size 4 x 10 x 10 mm) in a labelled (e.g.0001T Pax) cassette, then attach the cassette to the screw cap-rack assembly of the PAXgene Tissue Container and carefully submerge the rack into chamber 1 containing the PAXgene Tissue Fix. Screw the cap and leave the container at ambient temperature (20C – 220C) to fix for 2 – 4 hrs (depend on the size of the tissues). After fixation, transfer the cassette into chamber 2 containing the PAXgene Tissue Stabilizer and incubate at least 2 hrs before processing and embedding (see below for tissue processing procedures of PAXgene fixed tissues).

Note: The optimal fixation time is 2-4 hrs. However, if overnight fixation is necessary, the specimen can be fixed at 20C – 80C for up to 18 hrs. Longer fixation time and higher temperature may lead to degradation of biomolecules. For biopsies with a thickness of 1mm or less, fixation time can be reduced to 30 – 60 min.


Tissues are stable for a minimum of 3 and a maximum of 7 days at Room Temperature or for a minimum of 2 and a maximum of 4 weeks at 20C – 80C, depending on the type of tissue. Storage at -150C to -300C is also possible for at least 3 months without any negative effects on the morphology of the tissue or the integrity of the nucleic acids.


8 Collection and processing of metastatic lymph node (LN) (If applicable):

Cut a sample of lymph node tissue, then dissect it into ~5 mm3 cubes, place one cube per one sterile pre-labelled (e.g. 0001LN) tube (clear cap) , recap the tube tightly and snap freeze in liquid nitrogen




9 Once back at the lab, frozen and OCT samples are stored in numerical order in the -800C freezers and formalin samples are in 10% NBF jar to be batch processed by the Anatomical Pathology lab. PAXgene fixed tissues need to be transferred into PAXgene Stabilizer after 2 – 4 hours fixation at Room Temperature, and then stored at 40C fridge for batch processing, or frozen at -80 deg C.

PAXgene Fixed Tissue Processing Protocol

PAXgene fixed tissues are to be processed on a monthly basis or when the number of samples reaches 10 or more. The tissues are to be processed manually using the protocol below in Table 1 in a chemical fume hood. Fill each of the clean glass dishes to the top with the reagents in Table 1 and label accordingly. Leave the dishes with reagents in the chemical fume hood at all time during tissue processing. Place the PAXgene cassettes with tissues in the dishes and make sure the cassettes are fully submerged. Follow the Table below and bring the cassettes across all the reagents in the following order until the tissues are completely impregnated with wax.

Table 1. PAXgene Tissue Processing Protocol

Reagent Time Temperature

100% Ethanol 60 min 18-22ºc



Isopropanol 60 min 18-22ºc

Isopropanol 60 min 18-22ºc

Xylene 60 min 18-22ºc

Xylene 60 min 18-22ºc

Paraplast X-tra 60 min 56ºc



After the tissue processing procedures are completed, embed the tissue samples immediately into a block of paraffin using Paraplast X-tra. The embedding can be performed either manually or using Leica EG 1160 Embedding Station. After hardening of the paraffin, section the block and stain 1 x H&E stain for QC, then store paraffin blocks in the freezer box at -20 º c freezer. Archive the H&E slides in the slide drawers.


The PAXgene fixed tissue blocks can be used for general histology and Immunohistochemistry staining, in situ hybridisation, extraction and purification of DNA, RNA and miRNA using the associated kits from PreAnalytix. 10% NBF Fixed Tissue Processing Protocol The 10% NBF fixed tissues are batched and given to Anatomical Pathology Lab. Their staff will notify researchers when FFPE blocks and H&E stained slides when they are ready. One haematoxylin and eosin stained slide, a formalin-fixed paraffin-embedded tissue block or tissue core and a tissue sample preserved in a PAXgene® (PreAnalytiX) tissue container from the pre-treatment biopsy should be obtained and labelled with TROG study number, patient study number and initials.

Samples should be sent to:

Amy Chiang Scientist, MaCH R Tumour Bank

Clinical and Statewide Services Division | QueenslandHealth Level 1, Bldg 15, Pathology

Princess Alexandra Hospital Ipswich Rd, Woolloongabba QLD 4102

Ph: (Office) +61 7 3176 7142

or +61 7 3176 5847 Fax: +61 7 3176 2391

Email: [email protected] Web: http://tumourtissuebank.com


Appendix 13

Participant Information Sheet and Consent Form – Patient Preferences Survey

PARTICIPANT INFORMATION SHEET TROG 11.03 - A RANDOMISED PHASE III TRIAL OF HIGH DOSE PALLIATIVE

RADIOTHERAPY (HDPRT) VERSUS CONCURRENT CHEMOTHERAPY + HDPRT (C-HDPRT) IN PATIENTS WITH GOOD PERFORMANCE STATUS, LOCALLY ADVANCED /

SMALL VOLUME METASTATIC NSCLC NOT SUITABLE FOR RADICAL CHEMO-RADIOTHERAPY (P_LUNG GP)

PATIENT PREFERENCES SURVEY

Coordinated by the Trans Tasman Radiation Oncology Group (TROG) in collaboration with the Australian Lung Cancer Trials Group

1. Invitation

You are invited to take part in another component of this research study called a patient

preferences survey

Before you decide if you would like to take part in this part of the study you need to

understand why this research is being done and what it would involve for you. Please take

time to read the following information carefully and to decide if you wish to take part in the

study. Talk to others about the study if you wish and feel free to ask us if there is anything

that is not clear or if you would like more information.

You can use family [insert /whanau for New Zealand sites] support or a friend to help ask

questions and understand the study.

2. Why have I been invited?

You have already kindly agreed to take part in a research study comparing two different

ways of treating your lung cancer. Your cancer treatment may be taking either 21/2 weeks or

4 weeks to complete. The aim is to determine which of these treatments is better at

improving symptoms and quality of life.

3. What is the purpose of this component of the clinical research study?

The purpose of this part of the research study, the patient preferences survey, is to find out

how much improvement in your symptoms and quality of life YOU consider acceptable in


order to make the inconvenience of attending for each extra day of treatment worthwhile to

YOU.

Your opinion will be used to help guide decisions about lung cancer treatments in the future.

4. What does this study involve?

The study involves a telephone interview conducted by trained research staff employed by

the Hunter Valley Research Foundation. You will be asked to provide a telephone number

which will be conveyed to the research staff at the Hunter Valley Research Foundation. The

staff will contact you to arrange a suitable time for a telephone interview.

You will also be given a Patient Preferences survey booklet to read.

The survey booklet contains a number of hypothetical situations. Each hypothetical situation

will have a number of options. During the telephone interview, you will be asked to choose

which of the options you consider more acceptable for each situation

Ideally, you should read through the questionnaire and give some thought to your

preferences prior to being called. You may wish to mark your choices on the questionnaire,

which is fine, as you do not need to return it; the interviewer will record your choice over the

telephone.

It is important that you have the questionnaire in front of you when the interviewer calls. You

will be able to ask the interviewer any questions you may have regarding the survey.

The telephone interview will be undertaken before you commence treatment.

If you have prepared your answers in advance then the interview will be relatively quick.

However, the interview may take up to 20-30 minutes.

5. What are the possible risks from participating in the study?

It is not anticipated that there will be any risks from participating in this study.

Some patients may feel anxious or distressed during the study. If this is the case please

inform the research staff of any concerns you may have.

6. What are the possible benefits of participating in this study?

Your opinions may help to guide decisions about lung cancer treatment in the future.

7. What are the alternatives if I don’t want to take part in the study?

If you do not wish to take part in this study, you can still take part in the main research

project (looking at different ways of treating your lung cancer.


8. What will happen if I don’t want to carry on with this study?

You can completely withdraw from this study at any time, without having to give a reason.

You can notify the research staff of your decision at any time.

Withdrawal from this study WILL NOT jeopardize the treatment that you receive now or in

the future, your relationship with the staff caring for you or your ongoing care at this hospital.

9. Will my family doctor be involved?

It is desirable that your family doctor be advised of your decision to participate in this study.

By signing the Consent Form you agree to your family doctor being notified of your decision

to participate in this study.

10. How will my confidentiality be protected?

Any identifiable information that is collected about you in connection with this study will

remain confidential and will be disclosed only with your permission, or except as required by

law.

If you join the study, some information in your medical records and the data collected for the

study will be looked at by authorised persons as delegated by TROG - the group organising

the study. They may also be looked at by representatives of regulatory authorities.

11. What will happen with the results of the study?

It may be a number of years before the results of this research are available. When the

results are available they will be published as ‘journal articles’ in medical journals. Your

identity will not be revealed in these journal articles. Please ask your doctor if you want to

know more about this.

12. . Will participation cost me anything, and will I be paid?

Participation in this study will not result in any additional expense for you. You will not be

paid for your participation in this study.

13. Further information and contact details

Who do I contact for advice?

Please read this information sheet carefully. Feel free to ask for clarification on any aspect of

the study that you do not understand. Your doctor will answer any questions you may have.

You may also wish to discuss the study with a relative or friend or your local health worker.

Feel free to do this. Do not sign the consent form if you have not received satisfactory

answers to your questions and/or you have doubts about participating in this study.


Who do I contact for advice after hours?

If you have any medical problems during this project (for example, any side effects) and

need to speak to someone urgently after hours please contact:

Name

Contact Number 1

Contact Number 2

Who should I contact if I have concerns about the conduct of the study?

If you have any complaints about any aspect of the study, the way it is being conducted or

any questions about your rights as a research participant, then you may contact:

Ethics Coordinator: [Insert Name]


Or

Patient Advocate


You will need to tell the Ethics Coordinator or the Patient Advocate the name of the

researcher given on page 15 of this Participant Information and Consent Form.

Thank you for taking the time to consider being part of this study.

If you wish to take part in this study, please sign the attached consent form.

This information sheet is for you to keep.


CONSENT FORM TROG 11.03 - A RANDOMISED PHASE III TRIAL OF HIGH DOSE PALLIATIVE RADIOTHERAPY




PATIENT PREFERENCES SURVEY

By signing this consent form:

1. I confirm that I have read the Participant Information Sheet ([insert version number and date])

for the above study. I have had the opportunity to consider the information, ask questions and

have had these answered satisfactorily.

2. I understand that my participation is voluntary and that I am free to withdraw at any time

without giving any reason, without my medical care or legal rights being affected.

3. I understand that relevant sections of my medical notes and data collected during the study

may be looked at by individuals from TROG or from regulatory authorities where it is relevant to

my taking part in this research. I give permission for these individuals to have access to my

records.

4. I give permission for doctors, other health professionals, hospitals or laboratories outside this

hospital to release information concerning my disease and treatment that is needed for this

study. I understand that such information will remain confidential.

5. I agree to my family doctor being informed of my participation in the study

6. I agree to take part in the above study.

7. I understand that I will be given a signed copy of this document to keep.


Signatures













Appendix 14

Lung Cancer – Treatment Preferences Study

All the information provided in this survey is strictly confidential and only the researchers with direct involvement in the study will have

access to this information.

There is no need to return this questionnaire – you will be contacted by telephone


This survey is intended to tap into patient’s opinions about different durations of treatment when the aim of treatment is to relieve the symptoms caused by lung cancer and improve the quality of life of the patient. The treatment may not make the patient live any longer. We would like to find out how much improvement in symptoms and quality of life YOU would accept in order to make the inconvenience of each extra day of treatment (between shorter and longer treatment duration eg 21/2 weeks versus 4 weeks) worthwhile. Your responses to the following hypothetical treatment scenarios will be used to help guide decision about lung cancer treatments in the future. Lung cancer can cause the following symptoms: 1. Cough 2. Coughing up blood 3. Chest pain 4. Shortness of breath 5. Tiredness and loss of energy 6. Reduction in overall quality of life

Treatment for lung cancer can cause the following side effects 1. Pain when swallowing food or fluid

The survey contains hypothetical situations that describe symptoms which patients with lung cancer often experience. Whilst all the symptoms listed in the survey are possible, in reality, patients may not experience all of them, or in these particular combinations. The following situations have been made up for the purpose of this exercise. You may need to use your imagination for some. We would like you to imagine that you are talking to your doctor about how treatment will affect your symptoms and quality of life. Your doctor then offers you a choice between two hypothetical options with different effects on your symptoms and quality of life. We would like you to read the description of the two options and tell us which one you prefer (option A or option B). The first situation is an example; showing that all you need to do is tick a box.


Example Scenario

A B

Treatment type

1. Coming to the hospital 5 days a week for 2½ weeks (no treatment on weekends)

2. You will be at the hospital

for about 30 minutes each day

3. You will NOT have a small

needle inserted into a vein in your hand or arm

1. Coming to the hospital 5 days a week for 4 weeks (no treatment on weekends)


for about 30 minutes on four days and up to four hours on the fifth day

3. Once a week you will

have a small needle inserted into a vein in your arm or hand

After this treatment is finished, your symptoms will be....

Shortness of breath No shortness of breath even when climbing stairs

Shortness of breath quite a bit, even when resting

Coughing Coughing quite a lot Coughing a little bit

Coughing up blood Not coughing up blood at all Coughing up blood a little bit

Chest pain Quite a bit of pain in the chest No pain in the chest

The benefit of the treatment for your symptoms will last....

Duration of symptom improvement

Approximately 2 months Approximately 8 months

After this treatment is finished, your side effects will include....

Soreness when swallowing

Quite a bit of soreness when swallowing food or fluid

A little bit of soreness when swallowing food or fluid

Fatigue You need to rest quite a bit You need to rest a little bit

After this treatment is finished, your side effects will last for....

Duration of side effects Approximately 4 weeks Approximately 2 weeks

Which treatment would you prefer?

A B


Block 1; Scenario 1

A B

Treatment type




3.You will NOT have a small


1. Coming to the hospital 5 days a week for 4 weeks.(no treatment on weekends)



3. Once a week you will

have a small needle inserted into a vein in your hand or arm





Coughing up blood Coughing up blood a little bit

Not coughing up blood at all

Chest pain Quite a bit of pain in the chest

No pain in the chest








Fatigue You need to rest a little bit You need to rest quite a bit




A B


Block 1; Scenario 2

A B

Treatment type




3. Once a week you will have

a small needle inserted into a vein in your hand or arm







Shortness of breath No shortness of breath when resting, but quite a bit when walking

No shortness of breath when resting or walking but quite a bit when climbing stairs

Coughing Coughing a little bit Coughing quite a lot
















A B


Block 1; Scenario 5

A B

Treatment type



for about 30 minutes on four days and up to four hours on the fifth day.


a small needle inserted into a vein in your hand or arm.


2. You will be at the hospital for

about 30 minutes each day 3. You will NOT have a small

needle inserted into a vein in your hand or arm.


Shortness of breath No shortness of breath when resting or walking but quite a bit when climbing stairs

No shortness of breath even when climbing stairs


Coughing up blood Not coughing up blood at all

Coughing up blood a little bit














A B


Block 1; Scenario 8

A B

Treatment type




3. You will NOT have a

small needle inserted into a vein in your hand or arm












Chest pain No pain in the chest Quite a bit of pain in the chest












A B


Block 1; Scenario 9

A B

Treatment type





























A B


Block 1; Scenario 10

A B

Treatment type








about 30 minutes each day 3. 3. You will NOT have a small




















A B



A B

Treatment type





























A B



A B

Treatment type








about 30 minutes each day 3. You will NOT have a small



Shortness of breath Shortness of breath quite a bit, even when resting

No shortness of breath when resting, but quite a bit when walking

















A B



A B

Treatment type





























A B



A B

Treatment type






























A B


Block 2; Scenario 3

A B

Treatment type










a small needle inserted into a vein in your arm or hand




















A B


Block 2; Scenario 4

A B

Treatment type





a small needle inserted into a vein in your arm or hand
























A B


Block 2; Scenario 6

A B

Treatment type













Shortness of breath quite a bit even when resting

















Block 2; Scenario 7

A B

Treatment type


2. You will be at the hospital for about 30 minutes on four days and up to four hours on the fifth day

3. Once a week you will have a small needle inserted into a vein in you


2. You will be at the hospital for about 30 minutes each day

3. You will NOT have a small needle inserted into a vein in your hand or arm






















A B

Treatment type




























A B

Treatment type



























A B

Treatment type




























A B

Treatment type



























A B

Treatment type


2. You will be at the hospital for about 30 minutes each day;

























A B

Treatment type
























