2 STUDY …...185 SOP Standard Operating Procedure 186 SSE Significant safety event 187 TAH Total...

TABLE OF CONTENT 1

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Version 6 Stage 2 LACE Trial Date: May 2009 Page 2 of 96

LACE 4

LAPAROSCOPIC APPROACH TO CARCINOMA OF THE ENDOMETRIUM 5 AN INTERNATIONAL MULTICENTRE RANDOMISED PHASE 3 CLINICAL TRIAL 6

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

VERSION 6– MAY 2009 22

STAGE 2 23

CHIEF INVESTIGATOR: 24

PROF ANDREAS OBERMAIR MD FRANZCOG CGO 25 QUEENSLAND CENTRE FOR GYNAECOLOGICAL CANCER 26

BRISBANE, QUEENSLAND 27 AUSTRALIA 28

TEL: +61 7 3636 8501 29 FAX: ++61 7 3636 2307 30

EMAIL: [email protected] 31 32 33 PROPRIETARY NOTICE: 34 The concepts and information contained in this document or generated during the study 35 are considered proprietary and may not be disclosed in whole and in part without the 36 express written consent of Queensland Centre for Gynaecological Cancer, Brisbane, 37 Queensland, Australia. 38 39 40 ETHICS STATEMENT: 41 The study will be completed according to the guidelines of the Good Clinical Practice. 42 Compliance with this standard provides public assurance that the rights, safety and well 43 being of trial patients are protected, consistent with the principles that have their origin 44 in the Declaration of Helsinki 45

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TABLE OF CONTENTS 47

GLOSSARY OF ABBREVIATIONS ........................................................................................................................................ 6 48

protocol synopsis ........................................................................................................................................................................ 8 49

1 INTRODUCTION ............................................................................................................................................................ 10 50

1.1 DISEASE BACKGROUND ..................................................................................................................... 10 51

1.1.1 Public Health Impact ..................................................................................................................... 10 52

1.1.2 Disease Characteristics ................................................................................................................. 10 53

1.2 THERAPY BACKGROUND .................................................................................................................... 10 54

1.2.1 Total Abdominal Hysterectomy (TAH) ............................................................................................. 10 55

1.2.2 Laparoscopic Techniques: ............................................................................................................. 11 56

1.2.3 Total Laparoscopic Hysterectomy (TLH): ......................................................................................... 11 57

1.2.4 Lymph Node Dissection ................................................................................................................. 11 58

1.3 RATIONALE FOR THE STUDY .............................................................................................................. 11 59

2 STUDY OBJECTIVES ................................................................................................................................................... 12 60

2.1 STAGE 1 .............................................................................................................................................. 12 61

2.1.1 Primary Objective ......................................................................................................................... 12 62

3 STUDY PLAN .................................................................................................................................................................. 13 63

3.1 OVERALL DESIGN ............................................................................................................................... 13 64

4 STUDY TREATMENT ................................................................................................................................................... 13 65

4.1 STANDARD TREATMENT: TAH + PELVIC/AORTIC LYMPH NODE DISSECTION ..................................... 13 66

4.2 INTERVENTION: TLH + LAPAROSCOPIC PELVIC / AORTIC LYMPH NODE DISSECTION ....................... 14 67

4.3 PELVIC / AORTIC LYMPH NODE DISSECTION ...................................................................................... 15 68

4.4 ADJUVANT RADIOTHERAPY ................................................................................................................ 15 69

4.5 PARTICIPATING SURGEONS ............................................................................................................... 15 70

4.6 OUTCOMES ......................................................................................................................................... 16 71

4.6.1 Primary Outcome Measures ........................................................................................................... 16 72

4.6.2 Secondary Outcome Measures ...................................................................................................... 16 73

4.7 RANDOMISATION ................................................................................................................................ 17 74

4.8 SAMPLE SIZE ...................................................................................................................................... 18 75

4.9 STATISTICAL ANALYSES ..................................................................................................................... 18 76

4.10 ANALYSIS OF COST EFFECTIVENESS ............................................................................................ 19 77

4.11 ECONOMIC ANALYSIS ..................................................................................................................... 20 78

5 PATIENT ENROLLMENT ............................................................................................................................................. 20 79

5.1 INCLUSION CRITERIA .......................................................................................................................... 20 80


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5.2 EXCLUSION CRITERIA ......................................................................................................................... 21 81

6 STUDY VISITS ............................................................................................................................................................... 21 82

6.1 PRE-OPERATIVE (VISIT 1) ................................................................................................................... 21 83

6.2 SURGERY (VISIT 2) .............................................................................................................................. 22 84

6.3 POST-OPERATIVE (VISIT 3 -VISIT 5) .................................................................................................... 22 85

6.4 POST-OPERATIVE (VISIT 6) ................................................................................................................. 22 86

6.5 FOLLOW-UP VISITS ............................................................................................................................. 23 87

6.6 PATIENT WITHDRAWAL ....................................................................................................................... 24 88

7 STUDY ASSESSMENTS .............................................................................................................................................. 24 89

7.1 DEMOGRAPHICS, WEIGHT, MEDICAL HISTORY, PERFORMANCE STATUS AND PHYSICAL 90 EXAMINATION .............................................................................................................................................. 24 91

7.2 CHEST X-RAY ...................................................................................................................................... 25 92

7.3 CT SCAN / MRI / ULTRASOUND SCAN .................................................................................................. 25 93

7.4 ELECTROCARDIOGRAM ...................................................................................................................... 25 94

7.5 CLINICAL LABORATORY TESTS ........................................................................................................... 25 95

7.6 QUALITY OF LIFE INSTRUMENTS ........................................................................................................ 26 96

7.6.1 FACT-G ....................................................................................................................................... 26 97

7.6.2 EuroQoL-5d (EQ-5D) .................................................................................................................... 26 98

7.6.3 Pelvic Floor Distress Inventory (PFDI) ............................................................................................. 27 99

7.7 OTHER QUESTIONNAIRES .................................................................................................................. 27 100

7.7.1 Health Services Questionnaire (HSQ) ............................................................................................. 27 101

7.8 CONCOMITANT MEDICATION AND TREATMENT ................................................................................. 27 102

7.9 EFFICACY (DISEASE EVALUATION) ..................................................................................................... 27 103

8 ADVERSE EVENTS ...................................................................................................................................................... 28 104

8.1 DEFINITIONS ....................................................................................................................................... 28 105

8.1.1 Common Adverse Events .............................................................................................................. 28 106

8.1.2 Laboratory Test Abnormalities ........................................................................................................ 29 107

8.2 SERIOUS ADVERSE EVENTS ............................................................................................................... 29 108

8.3 ADVERSE EVENT REPORTING ............................................................................................................ 29 109

8.3.1 Obtaining Adverse Event Information .............................................................................................. 29 110

8.4 ASSESSMENT OF CAUSALITY ............................................................................................................. 30 111

8.5 ASSESSMENT OF SEVERITY ............................................................................................................... 30 112

8.6 SERIOUS ADVERSE EVENT REPORTING ............................................................................................. 30 113

8.7 CRITERIA FOR PREMATURE WITHDRAWAL ........................................................................................ 31 114

9 STUDY COMMITTEES ................................................................................................................................................. 32 115


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9.1 DATA SAFETY MONITORING COMMITTEE (DSMC) .............................................................................. 32 116

9.2 TRIAL MANGEMENT COMMITTEE (TMC) .............................................................................................. 32 117

10 DATA HANDLING AND QUALITY ASSURANCE ................................................................................................... 33 118

10.1 ELECTRONIC CASE REPORT FORMS ............................................................................................. 33 119

10.2 DATA SECURITY ............................................................................................................................. 33 120

10.3 ELECTRONIC SIGNATURES ............................................................................................................ 33 121

10.4 MONITORING OF THE STUDY ......................................................................................................... 34 122

10.5 INSPECTION OF RECORDS ............................................................................................................. 34 123

10.6 DATA QUALITY ASSURANCE ........................................................................................................... 34 124

10.7 STUDY RECORD RETENTION .......................................................................................................... 34 125

11 ADMINISTRATIVE CONSIDERATIONS ................................................................................................................... 35 126

11.1 CONFIDENTIALITY........................................................................................................................... 35 127

11.2 ETHICS APPROVAL ......................................................................................................................... 35 128

11.3 MODIFICATION OF THE PROTOCOL ................................................................................................ 35 129

11.4 INFORMED CONSENT ..................................................................................................................... 36 130

11.5 PROTOCOL VIOLATIONS AND DEVIATIONS .................................................................................... 36 131

11.6 STUDY REPORTING REQUIREMENTS ............................................................................................. 37 132

11.7 FINANCIAL DISCLOSURE AND OBLIGATIONS ................................................................................. 37 133

11.8 INVESTIGATOR DOCUMENTATION ................................................................................................. 37 134

11.9 STUDY CONDUCT ........................................................................................................................... 37 135

11.10 PUBLICATIONS ................................................................................................................................ 37 136

12 INVESTIGATOR’S STATEMENT OF AGREEMENT .............................................................................................. 38 137

APPENDIX 1: Schedule of Assessments ............................................................................................................................ 41 138

APPENDIX 2: GP Information Letter .................................................................................................................................... 42 139

APPENDIX 3: patient Information statement and consent form ...................................................................................... 44 140

APPENDIX 4: DEMOGRAPHICS FORM ............................................................................................................................ 47 141

APPENDIX 5: FACT G ............................................................................................................................................................ 49 142

APPENDIX 6: EURO-QOL 5D ............................................................................................................................................... 51 143

APPENDIX 7: HEALTH SERVICES QUESTIONNIARE .................................................................................................. 53 144

APPENDIX 8: PELVIC FLOOR DISTRESS INVENTORY ............................................................................................... 54 145

Appendix 9: LACE Stage 1 SUMMARY ............................................................................................................................... 56 146

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GLOSSARY OF ABBREVIATIONS 148 149

AE Adverse event 150

CA125 Cancer Antigen 125 151

CRF Case report form(s) 152

CONSORT Consolidated Standards of Reporting Trials 153

CT Computed tomography 154

CTCAE V3.0 Common terminology criteria for adverse events Version 3.0 155

DFS Disease free survival 156

DSMC Data safety monitoring committee 157

ECG Electrocardiogram 158

ECOG Eastern Cooperative Oncology Group 159

EQ-5D EuroQol-5D 160

eCRF Electronic case report form(s) 161

FACT-G Functional assessment of cancer therapy – general 162

FDA Food and Drug Administration 163

GCP Good clinical practices 164

HREC Human Research Ethics Committee 165

HSQ Health Services Questionnaire 166

IB Investigational brochure 167

ITT Intent to treat 168

LACE Laparoscopic approach to Carcinoma of the Endometrium 169

LFT Liver function test (s) 170

MRI Magnetic resonance imaging 171

NCI National Cancer Institute 172

ORR Overall response rate 173

OS Overall survival 174

PD Progressive disease 175

PET Positron Emission Tomography 176


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PFS Progression-free survival 177

PFDI Pelvic Floor Distress Inventory 178

PFS Progression-Free Survival 179

PS Performance status 180

QALY Quality Adjusted Life Years 181

QCGC Queensland Centre for Gynaecological Cancer 182

QOL Quality of life 183

SAE Serious adverse event 184

SOP Standard Operating Procedure 185

SSE Significant safety event 186

TAH Total Abdominal Hysterectomy 187

TGA Therapeutic Goods Administration 188

TMC Trial Management Committee 189

TLH Total Laparoscopic Hysterectomy 190

ULN Upper limit of normal 191

UQ University of Queensland 192

193

194

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protocol synopsis 196 Protocol Title LACE – Laparascopic Approach to Carcinoma of the Endometrium.

Full Protocol Title Laparoscopic Approach to Carcinoma of the Endometrium. An International Multicentre Randomised Phase 3 Clinical Trial.

Indication Endometrial Adenocarcinoma - FIGO Stage 1 (Grade 1, 2 and 3)

Primary Objective The primary objective of this trial is to assess disease-free survival at 4.5 years post-operatively for women with Stage 1 endometrial cancer, comparing patients who are randomised to receive Total Laparoscopic Hysterectomy (TLH) and patients who are randomised to receive Total Abdominal Hysterectomy (TAH).

Secondary Objectives • Comparing treatment morbidity between the two groups of patients;

• Assessing patterns of recurrence between the two groups of patients;

• Comparing the cost effectiveness of TLH compared to TAH;

• Assessing overall survival between arms;

• Comparing quality of life (QoL) between arms;

• Assessing pelvic floor function.

Study Design • International Multicentre

• Randomised (1:1)

• Phase 3 Two-Stage Clinical Trial. (STAGE 1 NOW COMPLETE – refer to Appendix 9)

• Stratification for site, FIGO stage and history of cancer.

• Assessing disease free survival at 4.5 years.

Planned Sample Size 755 patients using a 1:1 randomisation, with;

• 405 randomised to receive TLH and;

• 350 randomised to receive TAH.

Inclusion Criteria • Histologically confirmed primary endometrioid adenocarcinoma of the endometrium;

• Clinically stage I disease;

• Performance status of ECOG 0-1;

• Signed written informed consent;

• Females, aged 18 years or older.

Exclusion Criteria • Other histologic type than endometrioid adenocarcinoma of the endometrium;

• Clinically advanced disease (stages II-IV);

• Uterine size larger than 10 weeks gestation;

• Estimated life expectancy of less than 6 months;

• Enlarged aortic lymph nodes;

• Unfit for Surgery: serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator);

• Patient compliance and geographic proximity that do not allow adequate follow-up;

• Unfit to complete QoL measurements.


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Standard Treatment Total Abdominal hysterectomy (TAH) + pelvic/aortic lymph node dissection.

Experimental Treatment Total Laparoscopic Hysterectomy (TLH) + laparoscopic pelvic/aortic lymph node dissection.

Primary outcome Disease-free survival at 4.5 years follow-up.

Secondary outcomes Recurrence: Pattern/Site of recurrence

Morbidity: Intraoperative, perioperative, early postoperative (<4 weeks) and long-term morbidity (4 weeks to 12 months); transfusion requirements; postoperative pain and analgesic consumption.

Treatment Costs

Quality of Life: measured preoperatively and 4.5 years postoperative

Pelvic Floor Function

Survival: Overall Survival at 4.5 years follow-up.

Duration of the Study The study will be completed 4.5 years after surgery of the 755th patient to assess disease-free survival.

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1 INTRODUCTION 198

1.1 DISEASE BACKGROUND 199

1.1.1 PUBLIC HEALTH IMPACT 200

Endometrial cancer is the most common gynaecological malignancy in countries of the developed world with a 201

lifetime risk of 2.5% to 3% (1). Some 1,564 new cases were diagnosed in Australia in 2000 and the incidence of 202

endometrial cancer is steadily rising (2). Risk factors include older age, obesity, diabetes mellitus, nulliparity, 203

late menopause, unopposed oestrogen intake or oestrogen producing tumours, a history of breast cancer and 204

use of Tamoxifen (3, 4). 205

206

1.1.2 DISEASE CHARACTERISTICS 207

The vast majority of patients present with abnormal vaginal bleeding as an early symptom. Seventy-five percent 208

of the patients present with Stage I disease at diagnosis and their survival probability remains high with more 209

than 85% disease-free at 5 years from surgery (5). Prognosis depends on various factors, such as histological 210

grading, depth of invasion into the myometrium, lymph node involvement, the stage of disease and treatment 211

(for review see 3, 4). 212

213

The spread of endometrial cancer may be characterised by four different mechanisms including: 1. directly into 214

the myometrium of the uterus; 2. transtubal spread; 3. through lymphatic embolization into the pelvic lymph 215

nodes; and 4. rarely haematogenous into distant organs (liver, lungs) (3, 4). 216

217

Recurrence may be local (at the vault), in the pelvis, distant or at multiple sites. The median disease-free 218

interval is 15 months and 50% of all recurrences occur during the first 24 months after primary treatment (6). 219

Patients with recurrent disease can be rescued in 50-70% of cases with either surgery, radiotherapy, hormonal 220

therapy, chemotherapy or a combination of treatments (3, 4). 221

222

1.2 THERAPY BACKGROUND 223

1.2.1 TOTAL ABDOMINAL HYSTERECTOMY (TAH) 224

For patients with clinical stage I disease, removal of the uterus and both tubes and ovaries are considered 225

current standard treatment in Australia. The adnexa should also be removed because they might be a focus of 226

occult disease. 227

228

Staging of the disease is surgical and is often omitted in patients with very early disease. However, many 229

patients require surgical staging in order to determine the extent of the disease. This includes pelvic washings 230

(peritoneal cytology) and a pelvic and/or aortic lymph node dissection (for review see 5). Surgical staging aims 231

to detect occult disease in patients who are at risk of recurrence and who might benefit from radiation treatment 232


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postoperatively. Radiation can be given as brachytherapy to the vaginal vault, as external beam radiation to the 233

whole pelvis or as a combination of both. 234

235

Traditionally, surgery for endometrial cancer is performed through a laparotomy in most centres worldwide. A 236

vertical midline incision or a lower transverse incision (Pfannenstiel) followed by an extrafascial hysterectomy 237

are the most widely used techniques to remove the uterus, ovaries and the fallopian tubes (3, 4). 238

239

1.2.2 LAPAROSCOPIC TECHNIQUES: 240

When compared to laparotomy, recent evidence from both retrospective and prospective trials have shown the 241

laparoscopic approach to be feasible, safe and associated with less tissue trauma, lower estimated blood loss, 242

less pain and a shorter hospital stay (7-13). These studies compared laparoscopic assisted vaginal 243

hysterectomy (LAVH) with abdominal hysterectomy (TAH). Characteristically the operating time for LAVH is 244

longer when compared to TAH and the rate of intraoperative injury to the ureter and to the bladder may also be 245

higher during the initial learning period (learning curve). In addition, LAVH is thought to not always be feasible in 246

nulliparous patients and in patients with extraordinary obesity. 247

248

1.2.3 TOTAL LAPAROSCOPIC HYSTERECTOMY (TLH): 249

The technique of total laparoscopic hysterectomy (TLH), utilising the McCartney tube, has been developed by 250

Anthony J. McCartney over the last 10 years. It allows the completion of the hysterectomy entirely 251

laparoscopically, without the need for additional vaginal surgery (14, 15). In a recent study of patients with 252

endometrial cancer, a significantly decreased overall perioperative morbidity of 17% was observed in the 253

laparoscopy group compared to 43% in the laparotomy group (16). This effect was pronounced in patients 254

weighing 100 kg or more. In these obese patients, the wound infection rate was 2% in the TLH group and 255

almost 50% in the TAH group (17). This result is consistent with previous studies on obese endometrial cancer 256

patients (18-20). In another study, the disease-free survival and the patterns of recurrence were similar for 257

patients who underwent a TAH or a TLH (21). 258

259

1.2.4 LYMPH NODE DISSECTION 260

Transperitoneal laparoscopic pelvic and aortic lymph node dissection has been demonstrated to be both 261

feasible and safe. Initial reports on laparoscopic lymph node dissection were limited to pelvic lymph nodes (22) 262

but later reports described the feasibility of laparoscopic para-aortic lymph node dissection. Shortly thereafter 263

these techniques were adopted for the management of clinically stage I endometrial cancer (23-26). 264

265

1.3 RATIONALE FOR THE STUDY 266

Currently, a hysterectomy and bilateral salpingo-oophorectomy (± surgical staging ± postoperative radiation) is 267

the standard treatment for endometrial cancer. While this is an accepted effective treatment, a total abdominal 268

hysterectomy (TAH) is highly invasive, visibly scarring and is associated with tissue trauma, blood loss and a 269


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significant risk of wound and infectious adverse events (16,17). Additionally, TAH is associated with an average 270

hospital stay of approximately 5 to 7 days and an average recovery period (from surgery) of 5 to 6 weeks. 271

Considering that almost 2000 patients undergo a total abdominal hysterectomy for endometrial cancer every year 272

in Australia, the impact of such invasive surgery would influence a large number of women every year with 273

respect to their risk of treatment-related morbidity, recovery from surgery, length of hospital stay, as well as their 274

perceived post-operative Quality of Life. 275

276

Laparoscopic techniques have been demonstrated to be feasible and safe in the treatment of endometrial cancer, 277

with previous retrospective studies on TLH showing encouraging results (16, 17, 21). In a recent retrospective 278

series, the incidence of treatment-related morbidity was observed to be lower in patients who had total 279

laparoscopic hysterectomy (TLH) compared to patients who underwent a TAH (16). Retrospective data provides 280

evidence that the recurrence rate and patterns of recurrence are similar in patients who had a TLH or a TAH (21). 281

282

Treatment recommendations ideally are based on prospective, randomised trials comparing the current standard 283

technique (TAH) with the proposed better technique (TLH). However, there are currently no prospective studies 284

available which directly compare TLH against the standard treatment of TAH in regards to disease-free or overall 285

survival. 286

287

The data of this study will become the basis for assessing recurrence and disease-free survival. 288

289

2 STUDY OBJECTIVES 290

2.1 STAGE 1 291

2.1.1 PRIMARY OBJECTIVE 292

The primary objective is to assess disease-free survival at 4.5 years postoperatively for women with apparent 293

Stage 1 endometrial cancer, comparing patients who are randomised to receive Total Laparoscopic 294

Hysterectomy (TLH) and patients who are randomised to receive Total Abdominal Hysterectomy (TAH). 295

296

The primary hypothesis is that Total Laparoscopic Hysterectomy (TLH) is associated with equivalent disease-297

free survival when compared to the standard treatment of Total Abdominal Hysterectomy (TAH) for women with 298

apparent Stage I endometrial cancer. 299

300

The secondary hypotheses are: 301

• TLH is associated with equivalent or improved Quality of Life (QoL) at 6 months; 302

• TLH is associated with reduced treatment-related morbidity; 303

• TLH is associated with shorter hospital stay; 304

• TLH is associated with less analgesic consumption; 305


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• TLH is cost effective; 306

• TLH is associated with improved pelvic floor function. 307

308

3 STUDY PLAN 309

3.1 OVERALL DESIGN 310

This phase III international, multicenter, open-label, randomized clinical trial is an equivalence study with the hypothesis 311

that TLH is equivalent to TAH in terms of disease-free survival. 312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

Stage one of the trial has now been completed. For more information regarding Stage One please refer to Appendix 9. 337

338

4 STUDY TREATMENT 339

4.1 STANDARD TREATMENT: TAH + PELVIC/AORTIC LYMPH NODE DISSECTION 340

• Preoperatively thrombosis prophylaxis is given (as per institutional policy); 341

Informed Consent

Total Laparoscopic Hysterectomy (TLH)

Total Abdominal Hysterectomy (TAH)

Randomisation

405 patients 4.5 year follow-up

350 patients4.5 year follow-up

Assess:Disease free survival b Morbidity Recurrence Cost effectiveness Overall survival Quality of life a Post-op pain a Analgesic consumption a Pelvic floor functioning b

a = Stage 1, b = Stage 2


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• Preoperative antibiotic is given at least 15 minutes before skin incision; 342

• Positioning in the supine or lithotomy position; 343

• Vertical midline or lower transverse incision; 344

• Peritoneal cytology is obtained (normal saline); 345

• Extrafascial hysterectomy (Piver type 1) and bilateral salpingo-oophorectomy; 346

• Bulky, suspicious lymph nodes are removed if feasible; 347

o A pelvic lymph node dissection includes removal of the lymph nodes along the external iliac 348

artery, the internal iliac artery and the common iliac artery as well as in the obturator fossa; 349

o An aortic lymph node dissection for staging purposes would include removal of the lymphoid 350

tissue up to the level of the inferior mesenteric artery; 351

• Intra-abdominal drains are not mandatory; 352

• Mass closure of sheath, skin closure. 353

354

4.2 INTERVENTION: TLH + LAPAROSCOPIC PELVIC / AORTIC LYMPH NODE DISSECTION 355

• Preoperatively thrombosis prophylaxis is given(as per institutional policy); 356

• Preoperative antibiotic is given at least 15 minutes before skin incision; 357

• Positioning in the lower lithotomy position with the arms parallel to the patient or the arms resting on the 358

patient’s chest; 359

• One 12 mm subumbilical port, which carries the telescope plus two or three further 5 mm ports are 360

inserted; 361

• Surgical instruments include a hinged bipolar diathermy forceps, a monopolar pair of scissors, various 362

graspers, a laparoscopic needle holder and a suction-irrigation system; 363

• Diversion of the round ligament in order to enter the retroperitoneum; 364

• The ovarian pedicle is secured with bipolar diathermy and divided with monopolar scissors; 365

• The peritoneum of the broad ligament, both the anterior and the posterior leaves are divided with the 366

unipolar scissors; 367

• The incision is carried anteriorly and the bladder peritoneum is incised at the cervico-uterine junction; 368

• A tube with a diameter of 45 mm or 35 mm and a lid on its other end is inserted transvaginally; 369

• The bladder peritoneum is reflected and the bladder pillars are lateralised over the edge of the tube; 370

• The uterine artery is identified, secured and divided at the level of the rim of the tube; 371

• The vagina is circumcised over the vaginal tube and the specimen is removed through the vaginal tube; 372

• A systematic pelvic lymph node dissection is performed, which includes removal of external iliac nodes, 373

obturator nodes, and common iliac nodes ± removal of the aortic nodes up to the level of the inferior 374

mesenteric artery; 375

• The tube is used as a conduit to remove the lymph nodes from the abdominal cavity; 376


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• A needle suture is placed into the tube and the tube reinserted to the vaginal vault. Continuous 377

laparoscopic suture of the vault and associated peritoneum is performed while the CO2 378

pneumoperitoneum is maintained; 379

• The tube is removed and the knot is tied transvaginally. 380

381

4.3 PELVIC / AORTIC LYMPH NODE DISSECTION 382

Surgeons are required to perform pelvic ± para-aortic lymph node dissection as part of the treatment in both 383

arms; however surgeons can elect not to perform lymphadenectomy if patients meet any of the following 384

exemption criteria: 385

• Morbid Obesity; 386

• FIGO Stage 1A, Grade 1 (well-differentiated) or Grade 2 (moderately-differentiated); 387

• FIGO Stage 1B, Grade 1 (well-differentiated); 388

• Medically unfit for lymphadenectomy; 389

• Institutional Guidelines. 390

391

4.4 ADJUVANT RADIOTHERAPY 392

Findings at surgery are used to determine the need for radiotherapy in a purely adjuvant setting following 393

definitive surgery. In Europe it has been common practice to base the need for adjuvant radiotherapy on risk 394

determined by grade of tumour and myometrial invasion. In North America and Australia the decision is generally 395

based more on whether surgical staging has excluded extra-uterine disease and hence the risk of recurrence 396

(31). 397

398

The published data suggests that adjuvant radiotherapy is not indicated in the presence of low or intermediate 399

risk Stage 1 disease; however there is insufficient evidence to make recommendations or suggestions for 400

modifying local institutional guidelines regarding the use of post-hysterectomy radiotherapy based on other 401

tumour-related, patient-related, or treatment-related factors (31). 402

403

The delivery and management of radiation therapy will be carried out according to local institutional clinical 404

practice guidelines. Preliminary and final dosimetry information will be recorded. 405

406

4.5 PARTICIPATING SURGEONS 407

Participating surgeons are required to be qualified gynaecological oncologists with a proven track record in 408

clinical research to qualify as a surgeon for this clinical trial. In order to minimise surgical complications during a 409

surgeon’s initial learning phase, participating gynaecologic oncologists must provide evidence of a minimal 410

number of 20 supervised and documented TLHs performed as the main surgeon. 411

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It is expected that the number of international accredited surgeons will increase over the study period. These 413

surgeons will be assessed as to their experience with the laparoscopic technique before their participation in the 414

trial is approved. 415

416

4.6 OUTCOMES 417

4.6.1 PRIMARY OUTCOME MEASURES 418

Treatment equivalence as evaluated by: disease-free survival status at 4.5 years post-surgery, as measured by the 419

time interval between surgery and date of first recurrence. Confirmation of recurrent disease will be ascertained 420

through clinical assessment, radiological work-up and/or histological results. 421

422

4.6.2 SECONDARY OUTCOME MEASURES 423

• Patterns of recurrence: date and localisation of 1st recurrence – local, vault, pelvis, distal; 424

• Treatment related morbidity, as evaluated by: 425

- Intraoperative complications – injury to bladder, ureter, bowel; vascular injury and bleeding, 426

nerve injury; 427

- Perioperative (time to discharge from hospital): urinary tract infection, urinary retention, ileus, 428

cardiac (myocardial infarction, atrial fibrillation), pulmonary (oedema, atelectasis, pneumonia), 429

renal and cerebrovascular morbidity. Wound and vault complications (infection, breakdown, and 430

dehiscence). Septicaemia and thromboembolic complications (DVT, PE). Lymphocyst or abscess 431

formation; 432

- Early postoperative (< 4 weeks): Wound and vault complications (infection, dehiscence). 433

Lymphocyst, Abscess formation, Lymphoedema or Fistula formation; 434

- Long-term morbidity (4 weeks to 6 months): Lymphoedema, incisional hernia formation. 435

- Estimated blood loss: Haemoglobin change from baseline. A Full Blood Count (haemoglobin) 436

will be taken before and the morning after the operation; 437

- Postoperative pain and analgesic consumption; 438

• Cost-effectiveness; 439

• Quality of Life: Change in Quality of Life using Functional Assessment of Cancer General (FACT-G) 440

between baseline and 4.5 years after surgery. 441

• Pelvic Floor Distress Inventory: measures symptom severity and quality of life changes in women with pelvic 442

floor disorders. The Pelvic Floor Distress Inventory (PFDI) provides a standardized, reproducible 443

assessment of the patient’s symptoms and their effect on daily life. 444

• Overall survival at 4.5 years follow-up. 445

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4.7 RANDOMISATION 447

All eligible patients will be required to provide signed consent before being randomised. Prior to randomisation, 448

each patient will be screened for eligibility according to the inclusion and exclusion criteria. 449

450

The randomisation list will not be available from the study centre, statisticians, or the project team at QCGC. A 451

web-based computer randomisation procedure will be co-ordinated centrally by the School of Population Health, 452

University of Queensland, Brisbane, Australia. 453

454

STAGE 1 455

Randomised permuted blocks were used to allocate patients between the two treatment groups with an allocation 456

ratio of 2:1, favouring the intervention of TLH (mixed blocks of sizes 3 and 6). Randomisations were stratified 457

according to treating centre and by grade of differentiation (as taken from the endometrial biopsy/D&C). 458

459

STAGE 2 460

Permuted blocks will be utilised and to allocate patients between the two treatment groups with an allocation ratio 461

of 1:1. Randomisations will be stratified according to treating centre, grade of differentiation and history of cancer. 462

By the end of Stage II accrual, there will be approximately 55 more participants allocated to TLH as a result of 463

2:1 randomisation in Stage 1 of the trial. 464

465


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4.8 SAMPLE SIZE 466

The final sample size for Stage II has been determined to require 755 patients (405 TLH patients versus 350 TAH 467

patients). For the Stage I design of this trial (assessing equivalence in QoL outcomes) , a 2:1 randomisation 468

scheme was used to maximise the data collected on the TLH patients if the trial did not progress to Stage II. This 469

provided 180 patients by the completion of Stage I (120 allocated to TLH, 60 allocated to TAH). As Stage II 470

progressed from Stage I, a sample size of 640 patients was orginally targetted using a randomisation ratio of 471

0.76:1 for intervention: control in order to minimise the imbalance (would result in 370 TLH versus 270 TAH). 472

However, this strategy was soon deemed unfeasible for surgeons due to recruitment problems. As a 473

consequence, the randomisation ratio has been set to 1:1 for the remainder of the Stage II recruitment period. 474

475

Given this, the final sample size for the study has been determined to require 755 patients to declare equivalence 476

between the two surgical procedures with respect to the proportion surviving at 4 years. This sample size 477

assumes a final randomisation ratio of 0.86:1 (350 in TAH versus 405 in TLH) with 90% power, based on 60 478

months of patient accrual, 54 months of follow-up and a 5% Type I error. The sample size calculations have 479

been conducted by the trial statisticians at the NHMRC Clinical Trials Centre using ACCoRD software. 480

481

482

Power Accrual Time

(months)

Follow-up Time

(months) Randomisation ratio Total Sample Size TLH group TAH group

87% 54 54 0.76 730 415 315

85% 54 54 0.86 705 380 325

90% 54 54 0.86 775 415 360

90% 60 54 0.86 755 405 350

90% 60 60 0.86 705 380 325

483

Based on these numbers, for a 5-year accrual and 4.5-year follow-up, a total of 755 patients would be sufficient to 484

declare equivalence with an equivalence margin of 7% or less at 4.5 years. 485

486

4.9 STATISTICAL ANALYSES 487

Primary endpoints will be analysed according to the intention-to-treat principle. Descriptive statistics for QoL 488

overall (FACT-G) and subscales (physical well-being, social well-being, emotional well-being, functional well-489

being), will be calculated for each randomisation group at each assessment. Similarly, descriptive statistics will 490

also be calculated for other outcomes, such as pain scores, anxiety and depression scores and analgesic 491

Table for Option 1 Randomised Design


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consumption, etc. Continuous variables will be assessed for normality and equality of variances between groups. 492

Discrete variables (eg. presence/absence of post-operative infection) will be summarised by 493

frequencies/proportions. 494

495

For continuous variables, analysis of variance and/or regression will be used, where appropriate. If assumptions 496

for these tests are violated, alternative non-parametric tests will be used. Difference between groups with respect 497

to discrete variables will be evaluated by using chi-squared tests. 498

499

Analysis of disease-free survival, overall survival and other time to event endpoints (local control) will be analysed 500

using the method of Kaplan-Meier and (where appropriate) competing risks. 501

502

Exploratory analyses adjusting for prognostic factors including age, tumour size, stage, grade of differentiation, 503

depth of myometrial invasion, lymph node involvement, type of treatment, and ECOG status will be performed 504

using proportional hazards regression methods. The impact of baseline QoL on survival will also be investigated. 505

506

4.10 ANALYSIS OF COST EFFECTIVENESS 507

An assessment will be performed on the cost-effectiveness of TLH relative to TAH, calculated as the incremental 508

cost per unit of improvement in functional outcome, measured in terms of the primary outcome. This will assess 509

how much more money the proposed intervention will cost the health system and society, and whether this 510

represents a sound investment in terms of the improvement in quality of life. We will also measure the quality-511

adjusted life years (QALYs) gained with the intervention and use this to undertake a cost-utility analysis. The 512

QALY calculations will be based on health status measures for trial participants, with valuations of changes in 513

health status and quality of life based on the EQ-5D (Appendix 6). Several viewpoints will be considered for the 514

economic analyses, including those of health system purchasers, households and society in general. 515

516

In terms of measuring costs, a number of components will be considered, including: the intervention costs; GP 517

and specialist consultations; radiology and imaging; prescriptions, over-the-counter medications; community 518

health and social services; days off work; and informal care by family and friends. Direct costs will be obtained 519

for samples of patients, stratified by hospital, operation and outcome, using a bottom-up approach by recording 520

the volume of resource use in both arms of the trial, and then applying a unit cost to each component. Data on all 521

patients’ use of healthcare services will be collected using a combination of a retrospective questionnaire (Health 522

Services Questionnaire - Appendix 7) and clinical files. Where possible, local cost tariffs will be used and national 523

sources will be used as comparators. 524

525


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4.11 ECONOMIC ANALYSIS 526

We will assess the cost-effectiveness of the intervention (TLH ± Laparoscopic Pelvic/Aortic Lymph Node 527

Dissection) relative to standard treatment alone (TAH ± Pelvic/Aortic Lymph Node Dissection), calculated as the 528

incremental cost per unit of improvement in functional outcome, and measured in terms of the primary outcome. 529

530

The outcomes of this part of the economic analysis will be in terms of costs per disease and treatment specific 531

difference in quality of life at six months. More specifically, costs per fewer days’ treatment-related morbidity, 532

shorter hospital stays, less days with post-operative pain, and less analgesic consumption. This will assess the 533

difference in cost between the standard treatment and the proposed intervention to the health system and 534

society, and whether this represents a sound investment in terms of the improvement in quality of life. 535

536

We will also measure the quality-adjusted life years (QALYs) gained with the intervention and use this to 537

undertake a cost-utility analysis. The QALY calculations will be based on health status measures for trial 538

participants, with valuations of changes in health status and quality of life based on the EQ-5D [42]. Several 539

viewpoints will be considered for the economic analyses, including those of health system purchasers, 540

households and society in general. 541

542

This part of the economic analysis allows us to express outcomes in costs per QALY. The aim of this generic 543

outcome measure is to assess whether the study intervention represents value for money as compared to 544

alternative interventions (including for other conditions), and as compared to the various threshold values below 545

which an intervention is considered good value for money (in Australia $40,000 per QALY is often used). 546

547

5 PATIENT ENROLLMENT 548

The study population will compromise individuals who have endometrioid adenocarcinoma of the endometrium. 549

Approximately 755 patients will be enrolled at approximately 20 sites located in Australia, Hong Kong and New 550

Zealand. 551

552

Patients will be enrolled if they meet all of the inclusion criteria and none of the exclusion criteria. De-identified 553

information regarding excluded patients will be captured in accordance with the Consolidated Standards of 554

Reporting Trials (CONSORT Statement). 555

5.1 INCLUSION CRITERIA 556

Patients who may be included for this study must have the following: 557

• Histologically confirmed primary endometrioid adenocarcinoma of the endometrium; 558

• Clinically stage I disease; 559

• Performance status of ECOG 0-1; 560

• Signed written informed consent; 561


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• Females, aged 18 years or older. 562

563

5.2 EXCLUSION CRITERIA 564

Patients will be excluded from participating from the study if they have any of the following: 565

• Other histologic type than endometrioid adenocarcinoma of the endometrium; 566

• Clinically advanced disease (stages II-IV); 567

• Uterine size larger than 10 weeks gestation; 568

• Estimated life expectancy of less than 6 months; 569

• Enlarged aortic lymph nodes; 570

• Unfit for Surgery: serious concomitant systemic disorders incompatible with the study (at the discretion 571

of the investigator); 572

• Patient compliance and geographic proximity that allow adequate follow-up; 573

• Unfit to complete QoL measurements. 574

575

6 STUDY VISITS 576

Written consent will be obtained before any study specific procedures are undertaken. The study assessments that 577

occur at the following visits are described in Detail in Section 7. 578

579

6.1 PRE-OPERATIVE (VISIT 1) 580

The following procedures will be performed within 8 weeks of surgery 581

• Chest X-ray; 582

• CT scan and/or MRI Scan and/or PET Scan and/or Ultrasound of the abdomen and the pelvis 583

• Endometrial biopsy/ D&C (up to 12 weeks prior to surgery) 584

• Patients are screened for eligibility and required to sign informed consent form; 585

586

587

The following procedures will be performed within 28 days before surgery: 588

• Collect demographic data, medical history and concomitant illnesses (documented and graded 589

according to CTC Version 3); 590

• Record all medications (including prescription, over the counter remedies, vaccination, vitamin, or herbal 591

preparations) used presently and within the past 12 weeks; 592

• Administer Quality of Life instruments (FACT-G, EQ-5D, and PFDI) 593

• Conduct a complete physical examination; 594

• Assess patients for their individual ECOG performance score; 595

• Obtain weight (kg) and height (cm); 596


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• Perform blood test - Full blood count with haemoglobin, platelet count, haematocrit and erythrocyte 597

count, (coagulation profile if indicated), electrolytes, liver and kidney function tests and CA125 tumour 598

markers 599

• Perform 12-lead Electrocardiogram (if indicated); 600

• Complete Randomisation form that verifies the inclusion criteria have been met; 601

• Complete on-line randomisation procedures to randomise the patient and document the result. 602

603

6.2 SURGERY (VISIT 2) 604

The following procedures will be performed at this visit; 605

• Perform surgery as per Randomisation result: Standard or Intervention; 606

• Record intra-operative and post operative information (including operation details, histological findings, 607

intra-operative complications, transfusion details and any other special conditions around the operation). 608

• Record all intra-operative and post-operative medications given (no anaesthetic agents need to be 609

recorded – please refer to the completion guidelines for more detail). 610

611

6.3 POST-OPERATIVE (VISIT 3 -VISIT 5) 612

The following procedures will be performed at visits scheduled at 1 week, 4 weeks and 3 months after surgery (± 613

3 days). Please note these visits can either be performed directly in clinic or via telephone/mail: 614

• Administer Quality of Life instruments (EQ-5D); 615

• Administer Health Services Questionnaire (HSQ); 616


• Assess patients for their individual pain level using linear analogue scale; 618

• Obtain weight (kg); 619

• Record adverse events that have occurred or resolved (CTCAE v3.0); 620

• Update concomitant medications table recording any new medications or changes to existing 621

medications that have occurred in that period. 622

623

6.4 POST-OPERATIVE (VISIT 6) 624

The following procedures will be performed at visit 6 scheduled 6 months after surgery (± 3 days): 625

• Administer Quality of Life instruments (FACT-G, EQ-5D, Pelvic Floor Distress Inventory); 626

• Administer Health Services Questionnaire; 627


• Assess patients for their individual pain level using linear analogue scale; 629

• Obtain weight (kg); 630

• Record adverse events that have occurred or resolved (CTCAE v3.0); 631


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• Update concomitant medications records recording any new medications or changes to existing 632

medications that have occurred in that period. 633

634

6.5 FOLLOW-UP VISITS 635

Follow-up visits are scheduled every 3 months from Surgery for the first 2 years and every 6 months until year 636

4.5. Patients may either be seen directly at the treating clinic or by a specialist local to them. Data for follow-up 637

may therefore be obtained either directly in clinic or via correspondence with the treating physician. The main 638

consideration for follow-up is review of the patients’ disease status. 639

640

Follow-Up Visit Time from Surgery

1 9 months

2 12 months

3 15 months

**4 18 months

5 21 months

6 24 months

**7 30 months

8 36 months

**9 42 months

10 48 months

**11 54 months

641

The following procedures will be reviewed and documented at follow-up visits: 642

• Record any clinical assessments, radiological work-up and/or histology results 643

• If a recurrence is identified as a result of follow-up then the date of recurrence, its localisation and 644

treatment should be promptly recorded on the Relapse eCRF. In addition QCGC should be notified by 645

email within 24 hours of first being made aware of the recurrence. 646

• The date of death should also be recorded and every effort must be made to obtain a cause of death 647

(possibly disease-related, possibly treatment-related). Again, in the event of a patient death QCGC 648

should be notified within 24 hours. 649

650

As well as review of the information listed above the following procedures will also be performed at follow-up 651

visits 4, 7, 9 and 11 (scheduled 18, 30, 42 and 54 months after surgery (+/- 3 days): 652

• Administer Quality of Life instruments (FACT-G, Pelvic Floor Distress Inventory); 653

654

Table for Follow-up Visits schedule


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6.6 PATIENT WITHDRAWAL 655

Patients will be advised that they may voluntarily withdraw from the study at anytime, for any reason and it will not 656

affect their medical care. Patients are not obligated to reveal their reasons for withdrawal, but the Investigator 657

may request a letter from the patient noting her desire to withdraw from the study. The last known status of these 658

patients will be reported with the study results and all attempts to locate patients lost to follow up will also be 659

documented. 660

661

Patients will be informed that, should they withdraw from the study, they should remain under the care of an 662

appropriately experienced physician until the physician deems further follow-up unnecessary. 663

664

The following are circumstances for which a patient would be identified as not continuing her participation in the 665

study: 666

• Study Completed / Terminated 667

• Death 668

• Voluntary Withdrawal 669

• Unable to Return 670

• Unwilling to Return 671

• Intercurrent Illness 672

• Move to another area 673

• Lost to follow-up 674

• Other 675

If a patient relocates to another geographic area, which requires a change of physician, reasonable attempts will 676

be made to locate and request cooperation from a gynaecologist in order to complete follow-up. 677

678

7 STUDY ASSESSMENTS 679

7.1 DEMOGRAPHICS, WEIGHT, MEDICAL HISTORY, PERFORMANCE STATUS AND PHYSICAL 680

EXAMINATION 681

A demographic form will be provided to the patient prior to surgery to complete. 682

683

A complete medical history and physical examination will be conducted at Visit 1(Pre-Operative visit), as standard 684

preoperative procedure and will include assessments of the following organ/body systems: skin, head, ears, eyes, 685

nose, throat, neck, lymph nodes, pulse, chest, heart, abdomen, extremities, abdominal, musculoskeletal, and 686

general neurological examination. 687

688


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Weight will be measured and documented in kilograms at Visits 1, 3, 4, 5 and 6. Performance Status will be 689

assessed using ECOG performance score will also be assessed at Visits 1, 3, 4, 5 and 6 using a sliding linear 690

analogue pain scale. 691

692

For consistency, all efforts should be taken to have the physical examination performed by the same qualified 693

study staff at screening and final visits. 694

695

7.2 CHEST X-RAY 696

A standard Chest X-ray will be conducted at Visit 1 (Pre-Operative). If a chest x-ray is not performed a CT/MRI of 697

the chest will be an acceptable alternative. In either case, the Investigator or designee will be responsible for 698

reviewing the scan to assess whether it is within normal limits and to determine the clinical significance of the 699

results. This assessment will be recorded. For any clinically significant abnormal results, the Investigator must 700

contact the Chief Investigator to discuss the patient’s continued eligibility to participate in this protocol. 701

702

7.3 CT SCAN / MRI / ULTRASOUND SCAN 703

A CT scan and/or MRI (magnetic resonance imaging) and/or PET (Positron Emission Tomography)) and/or 704

Ultrasound scan of the abdomen/pelvis will be conducted at Visit 1 (Pre-Operative). The Investigator or designee 705

will be responsible for reviewing the scan to assess whether it is within normal limits and to determine the clinical 706

significance of the results. This assessment will be recorded. For any clinically significant abnormal scan results, 707

the Investigator must contact the Chief Investigator to discuss the patient’s continued eligibility to participate in 708

this protocol. 709

710

7.4 ELECTROCARDIOGRAM 711

A standard 12-lead ECG will be conducted at Visit 1 (Pre-Operative) if clinically indicated. The Investigator or 712

designee will be responsible for reviewing the ECG to assess whether it is within normal limits and to determine 713

the clinical significance of the results. This assessment will be recorded. For any clinically significant abnormal 714

ECG results, the Investigator must contact the Chief Investigator to discuss the patient’s continued eligibility to 715

participate in this protocol. 716

717

7.5 CLINICAL LABORATORY TESTS 718

All participants will have clinical laboratory tests for clinical chemistry, haematology, performed Visit 1 (Pre-719

Operative) at local laboratories which have established or generally acknowledged methods, normal reference 720

ranges, and quality control methods. 721

Clinical laboratory tests will include assessments of: 722

• Clinical chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate 723

aminotransferase, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, gamma glutamyl 724


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transferase, gamma globulin, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total 725

bilirubin, total protein, and uric acid. 726

• Haematology: red blood cell count, white blood cell count with differential, haemoglobin, haematocrit, 727

platelet count, and CA 125 tumour markers. 728

• Coagulation profile: prothrombin time, partial thromboplastin time, and INR will be conducted at Visit 1 729

(Pre-operative) if clinically indicated. 730

For the purpose of this study, patients will also be required to have a day one post-operative haemoglobin measurement 731

regardless of arm of treatment. Any further blood tests undertaken from the time the patient signs the consent form up 732

until 6 months after surgery will be recorded on the appropriate CRF regardless of relationship to study treatment. All 733

efforts should be made to record the test which coincides closest to the study time point. 734

735

7.6 QUALITY OF LIFE INSTRUMENTS 736

7.6.1 FACT-G 737

QoL issues may have important implications on the treatment of patients. Even if two treatment options may 738

have similar outcomes in terms of disease-free and overall survival, their QoL profiles might differ significantly. 739

In addition QoL measures could have prognostic value in patients with gynaecological cancer (28-30). 740

741

Patients treated for gynaecological cancer have been shown to suffer from compromised QoL (29). Sexual 742

arousal as well as body image was significantly reduced in patients who underwent treatment for endometrial 743

cancer compared to healthy controls (30). At present there is no (retrospective nor prospective) study 744

comparing QoL in patients undergoing TLH and TAH in patients with endometrial cancer. 745

746

The Centre on Outcomes, Research and Education (CORE) has developed a core measure to determine the 747

QoL of cancer patients, the Functional Assessment of Cancer Therapy-G (FACT-G) (27). The Fact-G has good 748

reliability (Chronbach’s alpha = 0.89; Test-Retest correlation = 0.92) and excellent validity (27). 749

750

The FACT-G will be administered by qualified study staff at Visits 1 and 6 then Follow-Up 4, 7, 9 and 11. For 751

details see Appendix 1. 752

753

7.6.2 EUROQOL-5D (EQ-5D) 754

EQ-5D is a standardised instrument for use as a measure of health outcome; it provides a descriptive profile 755

and a single index value for health status. EQ-5D will measure changes in health status and quality of life to 756

calculate the quality-adjusted life years (QALYs) gained with the intervention. 757

758

EQ-5D will be administered by qualified study staff at Visits 1, 3, 4, 5 and 6. For details see Appendix 1. 759

760


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7.6.3 PELVIC FLOOR DISTRESS INVENTORY (PFDI) 761

Measuring treatment specific symptom severity and quality of life changes is an important part of the evaluation 762

and treatment of women with gynaecological cancer. The Pelvic Floor Distress Inventory (PFDI) provides a 763

standardized, reproducible assessment of the patient’s symptoms and their effect on daily life (38). Use of this 764

psychometrically robust self-administered questionnaire is the most valid way of measuring the presence, 765

severity, and impact of a symptom or condition on a patient’s activities and well-being. 766

767

The PFDI will be administered by qualified staff at Visits 1 and 6 and Follow-Up 4, 7, 9 and 11. For details see 768

Appendix 1. 769

770

7.7 OTHER QUESTIONNAIRES 771

7.7.1 HEALTH SERVICES QUESTIONNAIRE (HSQ) 772

Seven items assessing health care utilization during the past 6 months were adapted from Health Care 773

Utilization items developed by the Stanford Patient Education Research Centre 774

(http://patienteducation.stanford.edu/research/utilization.html). The original items were reported to have to 775

excellent test-retest reliability ranging from 0.76-0.97 and to validly report use of such services (37). The HSQ 776

will be administered by qualified study staff at Visits 3, 4, 5 and 6. For details see Appendix 1. 777

778

7.8 CONCOMITANT MEDICATION AND TREATMENT 779

All concomitant medication(s) must be reported in the appropriate case report form. In addition, any diagnostic, 780

therapeutic or surgical procedures performed during the study period, should be recorded including the date, 781

indication, description of the procedure(s) and any clinical findings. Patients should receive full supportive care 782

including transfusions of blood and blood products, antibiotics, anti-emetics etc., where applicable. The reason(s) 783

for treatment and treatment dates should be recorded in the case report form. 784

785

Concomitant radiotherapy treatment and chemotherapy treatment is permitted and may be offered to patients 786

at the treating Investigator’s discretion according to each centre’s practice. Adherence to local institutional clinical 787

practice guidelines for the use of adjuvant radiotherapy is recommended. Treatment information has to be 788

recorded in the appropriate case report form. 789

790

7.9 EFFICACY (DISEASE EVALUATION) 791

A clinical evaluation will be performed before surgery, 4/6 weeks after surgery and then at 3 monthly intervals. 792

Evaluation may be performed at an earlier time point if clinical symptoms indicate. All imaging techniques (X-rays, 793

ultrasound, CT scans, MRI scans, PET scans and contrast studies), blood tests or other investigations which are 794

used in clinical practice are allowed for. 795

796


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Clinical assessment, radiological work-up ± histological confirmation will prove the presence of recurrent disease. 797

If a patient develops recurrent disease, the management of recurrence is entirely to the surgeon’s discretion, 798

although it will be performed according to current medical standard and it will be documented in the case report 799

forms. 800

801

8 ADVERSE EVENTS 802

8.1 DEFINITIONS 803

The Investigator is responsible for reporting all AEs that are observed or reported during the study, regardless of 804

their relationship to treatment or their clinical significance. 805

806

An AE is defined as “any untoward medical occurrence in a patient enrolled into this study regardless of its causal 807

relationship to study treatment”. Patients will be instructed to contact the Principal Investigator or Co-Investigator 808

at any time after surgery if any symptoms develop. 809

810

A treatment-emergent AE is defined as “any event not present prior to surgery or any event already present that 811

worsens in either intensity or frequency following surgery”. 812

813

All AEs that occur after surgery during the study must be reported in detail in the patient’s source/chart and on the 814

appropriate CRF and followed to satisfactory resolution or until the Principal Investigator or Co-Investigator 815

deems the event to be chronic or the patient to be stable. The description of the AE will include the onset date, 816

duration, date of resolution, severity, seriousness, aetiology, and the likelihood of relationship of the AE to study 817

treatment. 818

819

Intensity of adverse events will be graded using the National Cancer Institute Common Terminology Criteria for 820

Adverse Events version 3.0 (CTC-AE v3.0), and reported in detail as indicated on the CRF. 821

822

If an adverse event occurs which is not contained in the CTC-AE v3.0, the five-point scale below will be used: 823

1. Mild: discomfort noticed but no disruption of normal daily activity. 824

2. Moderate: discomfort sufficient to reduce or affect daily activity. 825

3. Severe: inability to work or perform normal daily activity 826

4. Life Threatening: represents an immediate threat to life 827

5. Death 828

829

8.1.1 COMMON ADVERSE EVENTS 830

The most common postoperative adverse events from study treatment include: 831

• Intraoperative injury (bowel, bladder, ureter, nerves or blood vessels) 832


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• Wound complication (vault or pelvic haematoma or collection) 833

• Infectious complications (bladder, chest, septicaemia) 834

• Postoperative haemorrhage/ bleeding, thromboembolic events (DVT, pulmonary embolus) 835

• Prolonged Ileus > 7 days, fistula formation (any) or hernia formation 836

• Cardiac, pulmonary renal or cerebrovascular complications 837

• Returned to theatre in same admission 838

839

8.1.2 LABORATORY TEST ABNORMALITIES 840

Laboratory test results will be recorded on the laboratory results section of the Case Report Form. Laboratory 841

test value abnormalities as such should not have to be reported in the AE section of the CRF as adverse 842

events, unless there is an associated clinical condition for which the patient is given treatment, concomitant 843

treatment is altered or the event is considered a serious adverse event. 844

845

8.2 SERIOUS ADVERSE EVENTS 846

An SAE is defined as “any event that results in death, is immediately life threatening requires inpatient 847

hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or 848

is a congenital anomaly/birth defect.” 849

850

Important medical events that may not result in death, be life-threatening, or require hospitalization may be 851

considered an SAE when, based upon appropriate medical judgment, they may jeopardise the patient and may 852

require medical or surgical intervention to prevent one of the outcomes listed in this definition. 853

854

8.3 ADVERSE EVENT REPORTING 855

Information regarding AEs will be collected from the time the patient signs the informed consent form up until 6 856

months post treatment. All AEs reported or observed during the study will be recorded as an AE in the patient’s 857

source/chart and CRF. Information to be collected includes drug treatment, type of event, time of onset, dosage, 858

investigator-specified assessment of severity and relationship to treatment, time of resolution of the event, 859

seriousness, as well as any required treatment or evaluations, and outcome. Adverse events resulting from 860

concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent medications, or progression of 861

disease states must also be reported. All AEs will be followed to adequate resolution. Any medical condition that 862

is present at the time that the patient is screened but does not deteriorate should not be reported as an AE. 863

However, if it deteriorates at any time during the study it should be recorded as an AE. 864

865

8.3.1 OBTAINING ADVERSE EVENT INFORMATION 866

At every study visit, patients will be asked a standard non-leading question to obtain any medically related 867

changes in their well being. They will also be asked if they have been hospitalised, had any accidents, used any 868


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new medications, or changed concomitant medication regimens (prescription, over-the-counter medications, 869

and herbal supplements). In addition to patient or Investigator observations, AEs will be documented from any 870

data collected (e.g., laboratory values, physical examination findings), or other documents that are relevant to 871

patient safety. 872

873

8.4 ASSESSMENT OF CAUSALITY 874

The Investigator’s assessment of an AE's relationship to treatment is part of the documentation process, but it is 875

not a factor in determining what is or is not reported in the study. If there is any doubt as to whether a clinical 876

observation is an AE, the event should be reported. 877

The relationship or association of the test article in causing or contributing to the AE will be characterized using 878

the following classification and criteria: 879

• Unrelated: This relationship suggests that there is no association between the surgery and the reported 880

event. 881

• Possible: This relationship suggests that treatment caused or contributed to the AE, i.e., the event 882

follows a reasonable temporal sequence from the time of surgery and/or follows a known response 883

pattern to the surgery, but could also have been produced by other factors. 884

• Probable: This relationship suggests that a reasonable temporal sequence of the event with drug 885

administration exists and the likely association of the event with the surgery. This will be based upon the 886

known or previously reported complications to the surgery, or judgment based on the Investigator’s 887

clinical experience. 888

• Definite: This relationship suggests that a definite causal relationship exists between the surgery and 889

the AE, and other conditions (concurrent illness, progression/expression of disease state, or concurrent 890

medication reaction) do not appear to explain the event. 891

892

8.5 ASSESSMENT OF SEVERITY 893

Adverse Event severity will be rated by the Investigator as mild, moderate, or severe using the National Cancer 894

Institute Common Terminology Criteria for Adverse Events version 3.0 (Appendix 7). Changes in the severity of 895

an AE should be documented to allow an assessment of the duration of the event at each level of intensity to be 896

performed. Adverse events characterized as intermittent require documentation of onset and duration of each 897

episode. 898

899

8.6 SERIOUS ADVERSE EVENT REPORTING 900

Any AE considered serious by the Principal Investigator or Co-Investigator or which meets the previous criteria 901

must be entered as an SAE on the adverse event section of the appropriate CRF in the electronic data capture 902

(EDC) system. The following must occur within one business day from the time that the site personnel first 903

become aware of the serious adverse event: 904


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• The site personnel in Australia, Hong Kong and New Zealand completes the SAE case report form 905

and faxes to: 906

Queensland Centre for Gynaecological Cancer (QCGC) 907

Data Management Office 908

Fax Number: ++61 7 3636 1721 909

910

The report to QCGC must be written and consist of the Serious Adverse Event Report Form and de-identified 911

data not entered in the eCRF (i.e., lab reports, ECG reports, etc). If the patient is hospitalized because of or 912

during the course of an SAE, then a copy of the hospital discharge summary should be faxed to QCGC as soon 913

as it becomes available. 914

915

Information regarding SAEs will be collected from the time the patient signs the informed consent form up until 6 916

weeks after surgery. After this time investigators must report only SAEs that they suspect could be attributed to 917

the study treatment. 918

919

All therapeutic measures will be at the discretion of the Principal Investigator or Co-Investigator. All reported 920

SAEs (related or not to the surgery) will be followed until satisfactory resolution or until the Principal Investigator 921

or Co-Investigator deems the event to be chronic or the patient to be stable. QCGC will be responsible for 922

reporting Serious Adverse Events to the other study sites. 923

924

8.7 CRITERIA FOR PREMATURE WITHDRAWAL 925

Patients have the right to withdraw from trial treatment or the study at any time for any reason. The investigator 926

also has the right to withdraw patients from trial treatment or the study in the event of intercurrent illness, adverse 927

events, protocol violations, cure, administrative reasons or other reasons. 928

An excessive rate of withdrawals can render the study uninterpretable; therefore, unnecessary withdrawal of 929

patients should be avoided. Should a patient decide to withdraw, all efforts will be made to complete and report 930

the observations as thoroughly as possible. The investigator should contact the patient either by telephone or 931

through a personal visit or a responsible relative must be contacted to determine as completely as possible the 932

reason for the withdrawal. 933

934

If a patients withdraws from the study, a complete final evaluation at the time of the patient’s withdrawal should be 935

made with an explanation of why the patient is withdrawing from trial treatment or the study. 936

If the reason for removal of a patient from the trial treatment or the study is an adverse event or an abnormal 937

laboratory test result, the principal specific event or test will be recorded on the Case Report Form. 938

939

In many instances patient withdrawal from the study constitutes a cessation of treatment and/or cessation of 940

completing associated forms such as quality of life. In these cases, permission should be obtained from patients 941


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by study staff to continue monitoring their disease state (relapse, survival, toxicity etc) via patient records as this 942

is a crucial component of the study for which consent was originally obtained. 943

944

9 STUDY COMMITTEES 945

9.1 DATA SAFETY MONITORING COMMITTEE (DSMC) 946

An independent Data Safety Monitoring Committee (DSMC) will be assembled to review the safety and efficacy 947

data collected during the study. They will be composed of individuals who are independent of the study and are 948

not involved (either directly or indirectly) in the management of this study. The membership includes the 949

following: 950

• 2 gynaecological oncologists; 951

• Statistician; 952

• A member of the ANZGOG Research Advisory Committee. 953

954

The DSMC will be responsible for monitoring, on an ongoing basis, any of the following events: 955

• General Toxicity (NCI-CTC AE, v3): grade 3 and grade 4 adverse events, serious adverse events; 956

• A patient death (grade 5). 957

958

The first safety analysis will be performed after 60 patients have completed treatment. All further DSMC meetings 959

should take place twice per year and the committee will review all safety data collected during the study. 960

961

Following each meeting, the committee will recommend to QCGC that the study continues according to the 962

protocol or may suggest changes to the protocol based on the outcome of the data review. In exceptional cases 963

the committee may recommend stopping the study due to safety reasons. 964

965

9.2 TRIAL MANGEMENT COMMITTEE (TMC) 966

A Trials Management Committee (TMC) will be assembled to review the trial’s progress. The TMC will consist of 967

the principal investigator, two associate investigators, a radiotherapist, a member of ANZGOG and the study 968

statistician, meeting/conferring every four months. 969

970

Following each meeting, the committee will recommend to QCGC that the study continues according to the 971

protocol or may suggest changes to the protocol based on the outcome of the data review. In exceptional cases 972

the committee may recommend stopping the study. 973

974


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10 DATA HANDLING AND QUALITY ASSURANCE 975

10.1 ELECTRONIC CASE REPORT FORMS 976

As part of the responsibilities assumed by participating in the study, the Investigator agrees to maintain adequate 977

case histories for the patients treated as part of the research under this protocol. The Investigator agrees to 978

maintain accurate source documentation and CRFs as part of the patient’s case history. 979

980

QCGC will supply the CRF. The CRF will be a web-based eCRF allowing geographically dispersed sites to 981

randomise participants, receive and transmit data to the central database at QCGC, Queensland, Australia in real 982

time. The e-CRF application has been be designed and implemented by QCGC in collaboration with the 983

University of Queensland in accordance with the U.S. Department of Health and Human Services Food and Drug 984

Administration’s (FDA) document: Guidance for Industry – Computerized Systems Used in Clinical Trials. 985

986

All requested information should be entered into the CRF within 48 hours of a patient visit. Detailed instructions 987

for completing the CRF will be distributed. If an item is not available or is not applicable, this fact should be 988

indicated. Blank spaces should not be present unless otherwise directed. Corrections to the CRF and the reason 989

for the change are tracked in an audit trial with the user’s log-in name and date and time the entry or correction is 990

made. The Investigator must review, sign, and date each completed CRF in a timely manner. The study monitors 991

will review the CRF at site visit. At the completion of the trial a copy of the CRF (PDF file on CDROM) will be 992

placed in the Investigator’s files. 993

994

10.2 DATA SECURITY 995

The administrative burden and security issues at sites will be greatly reduced as a result of reduced data storage 996

locally at sites. Data integrity is guaranteed through the use of transaction processing monitors, which allows for 997

multiple users to enter data while simultaneously guaranteeing the completeness of the data. 998

999

Access to this data base will be by password and will be restricted to trial personnel. An audit trail will be in place 1000

for generating, retaining, importing or exporting the electronic data. By implementing a good design and 128-bit 1001

Secure Socket Layer (SSL) encryption software, the most widely implemented encryption system for the Web at 1002

present (as used by government agencies and internet banking); the CRF will be extremely secure. 1003

1004

10.3 ELECTRONIC SIGNATURES 1005

The CRF will be compliant with all provisions of Food and Drug Administration's (FDA) part 11 of Title 21 of 1006

Regulations; Electronic Records; Electronic signatures that applies to records in electronic modified, maintained, 1007

archived, retrieved, or transmitted under any FDA regulations. 1008

1009


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10.4 MONITORING OF THE STUDY 1010

QCGC will closely follow the study. In doing so, QCGC or an appointed monitor will visit the Investigator and 1011

study facility at periodic intervals, in addition to maintaining necessary telephone and written contact as 1012

appropriate. The monitor will maintain a working knowledge of the study by way of observation, review of study 1013

records and source documentation, and discussion of the conduct of the study with the Investigator and staff. 1014

QCGC or its appointee will carefully monitor all aspects of the study for compliance with applicable government 1015

regulation with respect to current good clinical practice and current standard operating procedures. 1016

1017

10.5 INSPECTION OF RECORDS 1018

Investigators and institutions involved in the study will permit trial-related monitoring, audits, institutional Human 1019

Research Ethics Committee (HREC) review, and regulatory inspection(s) by providing direct access to source 1020

data/documents. In the event of an audit, the Investigator agrees to allow the Sponsor, its designee, the 1021

Therapeutic Goods Administration (TGA) or Food and Drug Administration (FDA), or other regulatory agency 1022

access to all study records. 1023

1024

The Investigator should promptly notify QCGC or its representative of any audits scheduled by any regulatory 1025

authorities and promptly forward copies of any audit reports received to QCGC. 1026

1027

10.6 DATA QUALITY ASSURANCE 1028

The overall procedures for quality assurance of clinical study data are described in the applicable Standard 1029

Operating Procedures (SOPs) and project specific procedures. Safety reporting will be done according to QCGC 1030

SOPs. Data management will be performed by QCGC in collaboration with University of Queensland. Accurate 1031

and reliable data collection will be assured by verification and cross–check of the CRFs against the investigator’s 1032

records by QCGC or its representative (source document verification). The data collected will be entered into the 1033

study database from the CRF. A comprehensive validation check program will verify the data and discrepancy 1034

reports will be generated accordingly for resolution by the investigator. 1035

1036

10.7 STUDY RECORD RETENTION 1037

Essential Documents should be retained at least 10 years after the study is completed. These documents should 1038

be retained for a longer period, however, if required by the applicable regulatory requirements or by an 1039

agreement with QCGC. It is the responsibility of the Principal Investigator at each site to make provisions for 1040

study record retention. It is the responsibility of QCGC to inform the Principal Investigator or Co-Investigators as 1041

to when these documents no longer need to be retained. 1042

1043


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11 ADMINISTRATIVE CONSIDERATIONS 1044

The following administrative items are meant to guide the Principal Investigator or Co-Investigator in the conduct of 1045

the trial but may be subject to change based on industry and government Standard Operating Procedures or 1046

Guidelines. Changes will be reported to the HREC but will not result in protocol amendments. 1047

1048

11.1 CONFIDENTIALITY 1049

All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner designed to 1050

maintain patient confidentiality. All records will be kept in a secure storage area with limited access. Clinical 1051

information will not be released without the written permission of the patient or the patient’s guardian, except as 1052

necessary for monitoring by QCGC or its representative, regulatory authorities, or the HREC. 1053

1054

The Investigator and all employees and co-workers involved with this study shall not disclose or use for any 1055

purpose, other than performance of the study, any data, records or other unpublished, confidential information 1056

disclosed to those individuals for the purpose of the study. 1057

1058

Prior written agreement from QCGC must be obtained for the disclosure of any said confidential information to 1059

other parties. 1060

1061

11.2 ETHICS APPROVAL 1062

Federal, state, and local regulations and ICH guidelines require that approval be obtained from an HREC prior to 1063

participation of human patients in research studies. Prior to the study onset, the HREC must approve the 1064

protocol, informed consent, advertisements to be used for patient recruitment, and any other written information 1065

regarding this study to be provided to the patient or the patient’s legal guardian. The site will maintain and make 1066

available for review by the Sponsor or its representative documentation of all HREC approvals and of the HREC 1067

compliance with Federal, state, and local regulations and ICH guidelines. 1068

1069

The Investigator is responsible for obtaining continued review of the clinical research at intervals not exceeding 1 1070

year or otherwise specified by the HREC. The Investigator must supply QCGC with written documentation of 1071

continued review of the clinical research. All HRECC approvals should be signed by the HREC Chairman and 1072

must identify the HREC name and address, the clinical protocol by title and/or protocol number and the date 1073

approval was granted. 1074

1075

11.3 MODIFICATION OF THE PROTOCOL 1076

The Sponsor or its designee must review and approve any changes in this research activity, except a necessary 1077

change to remove an apparent, immediate hazard to the patient. Amendments to the protocol must be submitted 1078

in writing to the Investigator’s HREC for approval prior to patients being enrolled into an amended protocol. 1079


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1080

11.4 INFORMED CONSENT 1081

A written informed consent shall be obtained from each patient prior to the patient’s entrance into the study. 1082

QCGC will provide an informed consent template to the investigative sites (Appendix 3). If the site makes any 1083

institution-specific modifications, QCGC may review the consent prior to HREC submission. The Investigator will 1084

submit the approved, revised consent to the appropriate HREC for review and approval prior to the start of the 1085

study. If the consent form is revised during the course of the study, all active participating patients must sign the 1086

revised form. 1087

1088

Before recruitment and enrolment, each prospective patient will be given a full explanation of the study and be 1089

allowed to read the approved informed consent form. The Investigator will inform the patient of the purpose of the 1090

study, randomisation of study groups and the follow-up schedule. The Investigator will discuss foreseeable risks 1091

involved, as well as potential benefits that result from the use of the new surgical technique. The Investigator will 1092

inform the patient that her medical records will be subject to review by government authorities, members of 1093

DSMC and by the HREC. 1094

1095

The patients will be informed by the Investigator that they are free to refuse participation in this study and, if they 1096

choose to participate, that they may withdraw from the study at any time without compromising further medical 1097

care. 1098

1099

Once the Investigator is assured that the individual understands the implications of participating in the study, the 1100

patient will be asked to give consent to participate in the study by signing the informed consent form. The 1101

Investigator shall provide a copy of the signed informed consent to the patient. The original form shall be 1102

maintained in the patient’s medical records at the site. 1103

1104

11.5 PROTOCOL VIOLATIONS AND DEVIATIONS 1105

The Investigator or designee should document and explain any deviation from the approved protocol. The 1106

Investigator may deviate from the protocol to eliminate an immediate hazard to trial patients without prior HREC 1107

approval. As soon as possible after such an occurrence, the Investigator should submit the implemented 1108

deviation or change, the reasons for it to the site HREC to QCGC, and to regulatory authorities, if required. 1109

1110

A deviation from the protocol is an unintended and/or unanticipated departure from the procedures and/or 1111

processes approved by the Sponsor and the HREC and agreed to by the Investigator. Deviations usually impact 1112

individual patients or a small group of patients and do not involve inclusion/exclusion or primary endpoint criteria. 1113

A protocol violation occurs when there is non-adherence to the protocol that results in a significant added risk to 1114

the patient, when the patient or Investigator has failed to adhere to major protocol requirements and the patient 1115


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was enrolled without prior QCGC approval, or when there is non-adherence to regulatory authorities’ regulations 1116

and/or ICH Good Clinical Practice (GCP) guidelines. 1117

1118

QCGC or its representative will document protocol violations and deviations during the monitoring visit and will 1119

notify the Investigator of violations and deviations verbally or in writing. The Investigator should notify the HREC 1120

of protocol violations and deviations in accordance with the HREC requirements. 1121

1122

11.6 STUDY REPORTING REQUIREMENTS 1123

By participating in this study, the Investigator agrees to submit reports of serious adverse events according to the 1124

timeline and method outlined in the protocol. In addition, the Investigator agrees to submit annual reports to their 1125

HREC as appropriate. 1126

1127

11.7 FINANCIAL DISCLOSURE AND OBLIGATIONS 1128

Investigators are required to provide financial disclosure information to QCGC and a commitment to promptly 1129

update this information if any relevant changes occur. 1130

1131

11.8 INVESTIGATOR DOCUMENTATION 1132

Prior to beginning the study, the Investigator will be asked to provide the following essential documents: 1133

• An original Investigator-signed Investigator’s Statement of Agreement (Section 12); 1134

• A HREC approved Informed Consent, samples of site advertisements for recruitment for this study, and 1135

any other written information regarding this study that is to be provided to the patient or legal guardians; 1136

• HREC approval; 1137

• Accurate and current curriculum vitae (CV) for the Investigator and each Co-Investigator; 1138

• Laboratory certifications and normal ranges for any laboratories used by the site; 1139

• Local institutional guidelines regarding the use of post-hysterectomy radiotherapy. 1140

1141

11.9 STUDY CONDUCT 1142

The Investigator agrees that the study will be conducted according to the principles of the ICH E6 Guideline on 1143

GCP and the principles of the World Medical Association Declaration of Helsinki. The Investigator will conduct all 1144

aspects of this study in accordance with all national, state, and local laws of the pertinent regulatory authorities. 1145

1146

The study will also comply with Australian requirements as set out in the NHMRC National Statement on Ethical 1147

Conduct in Research involving Humans (1999). 1148

1149

11.10 PUBLICATIONS 1150

Data will be published in peer-reviewed journals and presented at relevant national and international conferences. 1151

1152


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12 INVESTIGATOR’S STATEMENT OF AGREEMENT 1153 1154

I agree to conduct the study as outlined in the protocol entitled: 1155

“LACE – Laparoscopic Approach to Carcinoma of the Endometrium: An International Multicentre Randomised 1156 Phase 3 Clinical Trial, Version 5 Amendment 1 – December 2007” 1157

and in accordance with the guidelines and all applicable government regulations. 1158

I have read and understand all sections of the protocol including Section 10, Administrative Considerations. 1159

1160

1161

1162

_______________________________________________ 1163

Principal Investigator 1164

(Print name) 1165

1166

1167

________________________________________________ ______________________ 1168

Principal Investigator Date 1169

(Signature)1170


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References 1171

1. Jemal A, Thomas A, Murray T, Thun M: Cancer statistical 2002. CA Cancer J Clin 52: 23- 47,2002. 1172 2. Australian Institute of Health and Welfare (AIHW) and Australasian Association of Cancer Registries (AACR). 1173

Cancer survival in Australia, 2001. Part 1: National summary statistics. AIHW cat no. CAN 13. Canberra: 1174 Australian Institute of Health and Welfare (Cancer Series No. 18). 1175

3. Hacker NF: Uterine cancer. In Practical Gynecologic Oncology (Berek JS, Hacker NF, eds.), 3rd edition, 1176 Lippincott Williams & Wilkins, Philadelphia, 2000. 1177

4. Morrow CP, Curtin JP (Eds.): Synopsis of Gynecologic Oncology. Churchill Livingstone, New York 1998. Fifth 1178 Ed., pp 151-185. 1179

5. Creasman WT, Odicino F, Maisonneuve P, et al. International Federation of Gynecology and Obstetrics, 1180 Annual report on the results of treatment in gynecologic cancer. J Epidemiol Biostat 6:45-86, 2001. 1181

6. Aalders JG, Abeler V, Kolstad P: Recurrent adenocarcinoma of the endometrium: a clinical and 1182 histopathological study of 379 patients. 1183 Gynecol Oncol 17: 85-103, 1984 1184

7. Malur S, Possover M, Michels W, Schneider A: Laparoscopic-assisted vaginal versus abdominal surgery in 1185 patients with endometrial cancer – a prospective randomized trial. Gynecol Oncol 80: 239-244, 2001 1186

8. Marana R, Busacca M, Zupi E, et al.: Laparoscopically assisted vaginal hysterectomy versus total abdominal 1187 hysterectomy: a prospective, randomized, multicenter study. Am J Obstet Gynecol 180: 270-275, 1999 1188

9. Lumsden MA, Twaddle S, Hawthorn R, et al.: A randomised comparison and economic evaluation of 1189 laparoscopic-assisted hysterectomy and abdominal hysterectomy. BJOG 107: 1386-1391, 2000 1190

10. Spirtos NM, Schlaerth JB, Gross GM, et al.: Cost and quality-of-life analyses for early endometrial cancer: 1191 laparotomy versus laparoscopy. Am J Obstet Gynecol 174: 1795-1800, 1996 1192

11. Ottosen C, Lingman G, Ottosen L: Three methods for hysterectomy: a randomised, prospective study of short 1193 term outcome. BJOG 107: 1380-1385, 2000 1194

12. Mäkinen J, Johanson J, Tomas C, et al.: Morbidity of 110 hysterectomies by type of approach. Hum Reprod 1195 16: 1473-1478, 2001 1196

13. Magrina JF, Serrano L, Cornella JL: Laparoscopic lymphadenectomy and radical or modified radical vaginal 1197 hysterectomy for endometrial and cervical carcinoma - preliminary experience. J Gynecol Surg 11:147-151, 1198 1995 1199

14. McCartney AJ, Obermair A: Total laparoscopic hysterectomy with a transvaginal tube. J Am Assoc Gynecol 1200 Laparosc 11:79-82, 2004. 1201

15. McCartney AJ, Johnson N: Using a vaginal tube to exteriorize lymph nodes during a laparoscopic pelvic 1202 lymphadenectomy. Gynecol Oncol 57: 304-306, 1995. 1203

16. Manolitsas TP, McCartney AJ: Total laparoscopic hysterectomy in the management of endometrial carcinoma. 1204 J Am Assoc Gynecol Laparosc 9: 54-62, 2002 1205

17. Obermair A, Manolitsas TP, Leung Y, Hammond IG, McCartney AJ: Total Laparoscopic Hysterectomy vs. 1206 Total abdominal hysterectomy for obese women with endometrial cancer. Submitted for publication. 1207

18. Eltabakh GH, Shamonki MI, Moody JM, Garafano LL: Hysterectomy for obese women with endometrial 1208 cancer: laparoscopy or laparotomy. Gynecol Oncol 78: 329-335, 2000 1209

19. Holub Z, Bartos P, Jabor A, et al.: Laparoscopic surgery in obese women with endometrial cancer. J Am 1210 Assoc Gynecol Laparosc 7: 83-88, 2002 1211

20. Ostrzenski A: Laparoscopic total abdominal hysterectomy in morbidly obese women. J Reprod Med 44: 853-1212 858, 1999 1213

21. Obermair A, Manolitsas TP, Leung Y, Hammond IG, McCartney AJ: Total laparoscopic hysterectomy for 1214 endometrial cancer: patterns of recurrence and survival. Gynecol Oncol 92: 789-793, 2004 1215


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22. Querleu D Leblanc E, Castelain B: Laparoscopic pelvic lymphadenectomy in the staging of early carcinoma of 1216 the cervix. Am J Obstet Gynecol 164: 579-581, 1991 1217

23. Childers JM, Brzechffa PR, Hatch KD, Surwit EA: Laparoscopically assisted surgical staging (LASS) of 1218 endometrial cancer. Gynecol Oncol 51: 33-38, 1993 1219

24. Fowler LM, Carter JR, Carlson JW, Maslonkowski R, Byers LJ, Twiggs LB: Lymph node yield from 1220 laparoscopic lymphadenectomy in cervical cancer: a comparative study. Gynecol Oncol 51: 187-192, 1993 1221

25. Chon Taik Park, Lim KT, Chung HW, Lee KH, Seong SJ, Shim JU, Kim TJ: Clinical Evaluation of 1222 laparoscopic-assisted radical vaginal hysterectomy with pelvic and/or paraaortic lymphadenectomy. J Am 1223 Assoc Gynecol Laparposc 9: 49-53, 2002. 1224

26. Possover M, Krause N, Kuehne-Heid R, Schneider A: Value of laparoscopic evaluation of paraaortic and 1225 pelvic lymph nodes for treatment of cervical cancer. Am J Obstet Gynecol 178: 806-810, 1998 1226

27. Cella D, Hahn EA, Dineen K: Meaningful change in cancer-specific quality of life scores: differences between 1227 improvement and worsening. Qual Life Res 11; 207-21, 2002. 1228

28. Andersen BL: Psychological interventions for cancer patients to enhance the quality of life. J Consult Clin 1229 Psychol 60: 552-568, 1992 1230

29. Andersen BL, Andersen B, deProsse C: Controlled prospective longitudinal study of women with cancer: II. 1231 psychological outcomes. J Consult Clin Psychol 57: 692-997, 1989 1232

30. Cochran SD, Hacker NF, Wellisch DK, Berek JS: Sexual functioning after treatment for endometrial cancer. J 1233 Psychosoc Oncol 5: 347-353, 1987 1234

31. Kitchner H, Jones III HW, Bertelsen K, Aalders J, Quinn M, Creutzberg C, Heatley M: Cancer of the Corpus 1235 Uteri. In Staging classifications and clinical practice guidelines of gynaecologic cancers. Edited by Benedet 1236 JL, Hacker NF, Ngan HYS. FIGO Committee on Gynaecologic Oncology, 2000, pp 59-79. 1237

32. Herrmann C. International experiences with the hospital anxiety and depression scale - a review of validation 1238 data and clinical results. J Psychosom Research 1997; 42: 17-41. 1239

33. Maher EJ, Mackenzie C, Young T, et al. The use of the Hospital Anxiety and Depression Sale (HADS) and the 1240 EORTC QLQ-C30 questionnaire to screen for untreatable unmet needs in patients attending routinely for 1241 radiotherapy. Cancer Treatment Reviews 1996; 22: 123-129. 1242

34. Skarstein J, Aass N, Fossa SD, et al. Anxiety and depression in cancer patients: relation between the hospital 1243 anxiety and depression scale and the European organization for research and treatment of cancer core quality 1244 of life questionnaire. J Psychosom Research 2000; 49: 27-34. 1245

35. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361-370. 1246

36. Hopwood, P., Fletcher, I., Lee, A., & Al Ghazal, S. (2001). A body image scale for use with cancer patients. 1247 European Journal of Cancer, 27, 189-197. 1248

37. Ritter PL, Kaymaz H, Stewart A, Sobel DS, Lorig KR, Self-reports of health care utilization compared to 1249 provider records. Journal of Clinical Epidemiology, 2001, 54, pp.136-141. 1250

38. Barber MD, Waters MD, Bump RC. Short forms of two condition-specific quality-of-life questionnaires for women with 1251 pelvic floor disorders. American Journal of Obstetrics and Gynecology, 2005, 93(1), pp.103-13.1252


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APPENDIX 1: Schedule of Assessments 1253 1254

Evaluation / Examination Pre-Op Baseline Post-op Follow-up 1 week 4 weeks 3 months 6 months

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6Informed Consent Xb

Inclusion/Exclusion Criteria Xb

Medical History Xb

Physical Examination Xb

Height Xb

Weight Xb

X X X X

ECOG PS Xb

X X X X

Concomitant illnesses Xb

X X X X

Concomitant medications Xb

X X X X

FBC Xb

Xc Xc Xc Xc

U&E, E/LFT Xb

Xc Xc Xc Xc

CA125 Xb

ECG Xb,c

Chest X-Ray Xa

CT or MRI or PET or Ultrasound Scan Abdomen and Pelvis

Xa

Endometrial Biopsy / D&C Xa

FACT-G Xb

X**Follow Up 4, 7, 9, 11

EQ-5D Xb

X X X X

Health Services Questionnaire

X X X X

Pelvic Floor Distress Inventory Xb

X**Follow Up 4, 7, 9, 11.

Demographics of Patients with Endometrial Cancer

Xb

Surgical Treatment (TLH or TAH) X

Operative Details X

Pain Scale (linear analogue scale)

X X X X

Treatment-related Morbidity

X X X X

Patient’s Disease Status

X

a= Up to 8 weeks before surgery b = Within 28 days of surgery c = If clinically indicated** The Fact-G and Pelvic Floor Distress Inventory will be provided at V1, 6 then at Follow-up 4, 7, 9 and 11 only.

1255

1256


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APPENDIX 2: GP Information Letter 1257

LACE – Laparoscopic Approach to Carcinoma of the Endometrium 1258 An International Multicentre Randomised Phase 3 Clinical Trial 1259

Information for General Practitioners 1260

1261

Patient’s Name: ………………………………………………………………….….….….

Hospital Number: ……………………………………………………………………………

This is a randomised trial comparing two surgical techniques for the treatment of endometrial cancer. Method 1 is the standard 1262

approach worldwide and consists of a laparotomy through a vertical midline incision or a lower transverse abdominal incision. 1263

Method 2 is a new method, where the operation is performed laparoscopically. Results achieved with laparoscopic hysterectomies 1264

during the past year have been extremely encouraging. Manuscripts on the new technique have been accepted for publication and 1265

the authors feel that a randomised trial is warranted. 1266

The primary hypothesis is that Total Laparoscopic Hysterectomy (TLH) is associated with equivalent or improved Quality of Life 1267

(QoL) at 6 months and equivalent disease-free survival when compared to the standard treatment of Total Abdominal 1268

Hysterectomy (TAH) for women with Stage I endometrial cancer. 1269

The secondary aims of the study include establishing if compared to women receiving TAH if TLH is associated with: 1270

• Reduced treatment-related morbidity 1271 • Shorter hospital stay 1272 • Less post-operative pain 1273 • Less analgesic consumption 1274

Your patient has kindly agreed to take part in this trial and has been randomised to: 1275

1276

Total Laparoscopic Hysterectomy Total Abdominal Hysterectomy 1277

1278

You will be kept informed of your patient’s progress and the only difference from standard treatment is that your patient will be 1279 asked to complete regular quality of life questionnaires at certain intervals. If you have any further queries about this trial please do 1280 not hesitate to contact the responsible clinician: 1281

1282


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............................................................................... ........................................................................................ 1283

Name of Clinician Name of Hospital 1284 ………………………………………………………………………… 1285 Telephone 1286 1287


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APPENDIX 3: patient Information statement and consent form 1288

1289

INSTITUITION NAME 1290 PATIENT INFORMATION STATEMENT 1291


PRINCIPAL INVESTIGATOR: PI Name 1294 1295

Participant Selection and Purpose of Study 1296

You are invited to participate in a study comparing two different surgical techniques for the treatment of endometrial 1297 (uterine) cancer. You were selected as a possible participant in this study because you were diagnosed with endometrial 1298 cancer on a recent D&C or a sampling of endometrial cells from the uterus. The work-up has revealed no spread of 1299 tumour and an “early” cancer is anticipated. The standard treatment of this condition is surgery. 1300

Two surgical techniques are available: 1301

Method 1: Most centres worldwide would open the abdomen through a vertical incision or a lower transverse incision 1302 and remove the uterus, the fallopian tubes and the ovaries. While you are still under anaesthetic (asleep) an assessment 1303 of the uterus is performed during the operation and the results of this assessment are reported to the surgeon in the 1304 operating theatre. Your surgeon will make a decision whether to remove some lymph nodes in the pelvis. 1305 1306

Method 2: The other method is a new method and it is called laparoscopy (“keyhole surgery”) where no big incision 1307 needs to be done through the abdomen. The surgery is carried out through little incisions in the abdomen, none of which 1308 is larger than 1 cm. A camera is inserted into the abdomen and the surgeon controls the operation on a screen to which 1309 the images of inside the abdomen are transferred. The extent of the operation is exactly the same as with the method 1310 above. Your surgeon will remove the uterus, the fallopian tubes and the ovaries. While you are still under anaesthetic 1311 (asleep) an assessment of the uterus is performed during the operation and the results of this assessment are reported 1312 to the surgeon in the operating theatre. Your surgeon will make a decision whether to remove some lymph nodes in the 1313 pelvis. 1314 1315 We have performed laparoscopic surgery very often and we are encouraged by the preliminary results. Our preliminary 1316 data have shown that laparoscopic treatment of early endometrial cancer can be done, it is safe and it may have 1317 potential advantages for patients. Additional data have shown that no difference exists in the prognosis of patients with 1318 endometrial cancer when they had laparoscopic or open surgery. However, no formal comparison has been made 1319 between laparoscopic and open surgery in this patients’ group. 1320

1321

Therefore we want to compare both techniques to demonstrate that both techniques are equally effective in terms of 1322 prognosis but superior with respect to quality of life and treatment-related morbidity of surgery. Without such a formal 1323 comparison (clinical trial), final treatment recommendations cannot be made. 1324

1325 1326

1327 1328


- Confidential -


What does the study involve? 1329

Should you agree to this important study, you will be asked to sign an informed consent. You will be randomly allocated 1330 to one of the two groups (laparoscopy or open surgery) with an equal chance being allocated to either group. Your 1331 surgeon and you will not know until the day before surgery which type of surgery you will have. This “randomisation” 1332 guarantees that a fair and balanced comparison can be made between the two different surgical groups. If 1333 randomisation would not be possible, the outcomes of the study would be flawed and irrelevant for patients with 1334 endometrial cancer in Country. 1335

1336

The preoperative work-up for both groups includes medical work-up, blood tests, X-rays, CT or an MRI scan and an 1337 ECG. The preoperative work-up is exactly the same for both groups and reflects our routine protocol. In addition to the 1338 routine protocol we ask you to complete a questionnaire taking approximately 20 minutes of your time about your quality 1339 of life before surgery and again 1 week, 6 weeks, 3 months, 6 months, 1.5 years, 2.5 years, 3.5 years and 4.5 years 1340 after surgery. We will also collect some information about your personal background such as your marital status and 1341 your education, as we know from previous research that this may influence people’s quality of life. 1342

1343

No difference would be made with respect to the recommendation of postoperative treatment (radiotherapy, 1344 chemotherapy) and your follow-up between the two treatment modalities. 1345

What are the possible risks if I take part? 1346

Every intervention (surgery) carries risks. Apart from medical and anaesthetic risks we also know of surgical risks. 1347 Uncommon events include injury to the bowel, the bladder, the ureter, nerves or large blood vessels. These injuries 1348 usually are corrected at the time of initial surgery but sometimes another operation is required. More commonly 1349 infections to the skin, the lungs or the bladder may occur. Therefore we administer antibiotics prior to surgery. We also 1350 give blood-thinning medication after surgery in order to prevent unwanted blood clots. 1351 1352 Preliminary data has shown that the risk of infections is lower in patients who had a laparoscopic procedure than in 1353 patients requiring open surgery. All other risks are similar. However, there is a risk of 5% to 10% that the operation 1354 needs to be converted to an open procedure if a laparoscopy was aimed for. Usually, a procedure is converted because 1355 of unexpected difficulties at surgery (adhesions, bleeding). 1356 1357 What are the potential benefits if I take part? 1358

You may or may not experience a direct medical benefit from your treatment. If you take part you will help to provide 1359 information that may lead to a better understanding of how to treat future patients with your condition. 1360 1361

Will my taking part in this study be kept confidential? 1362 All aspects of the study, including results, will be strictly confidential and only your doctors and the staff involved in the study will 1363 have access to information on participants. A report of the study may be submitted for publication, but individual participants will 1364 not be identifiable in such a report. 1365

1366

1367

1368


- Confidential -


All or part of your medical records will be sent to a Safety Committee to be reviewed and analysed by clinicians and other study 1369 personnel, along with the records of all other people participating in this study from this and other institutions. Portions of your 1370 medical information may be transmitted electronically through the Internet, but this information will be encrypted (scrambled) to 1371 maintain confidentiality. 1372

Your hospital records, doctor's office records, laboratory records, operating room and other records may be audited by 1373 representatives of the following organisations: 1374

• Local Regulatory Authority, or 1375 • Australian Therapeutic Goods Administration (TGA), or 1376 • Institutional Human Ethics and Research Committee 1377

These and the Trials Data Safety Committee may review the research to see that it being done safely and correctly. The 1378 representatives of these organisations all comply with privacy standards. 1379

The Data Safety Committee, an independent group of experts, will be reviewing the data from this research on an ongoing basis. If 1380 any important new information about the study develops that may affect your health, welfare, or willingness to stay on the study, 1381 your doctor will tell you. You may be asked to sign another consent form at that time. 1382

1383 What are the costs of being involved? 1384 Your participation in this study will not influence the amount of money (if any) you have to pay for your treatment at this institution. 1385 You will not be paid for taking part in the study. If any complications of the disease or treatment occur, the hospital will provide 1386 appropriate treatment for these problems. 1387

1388

What are my rights as a participant? 1389 Even after you agree to take part in this study, you may withdraw at any time. Before you withdraw, you should first talk to one of 1390 the researchers or nurses involved. This will allow them to inform you of any medical problems that could result when treatment 1391 stops. You can choose to withdraw one of two ways. You can stop your study treatment, but still allow the study doctor to follow 1392 your care. Alternatively, you can stop your study treatment and not have any further contact with the study staff. Either way, your 1393 decision will not affect your medical treatment or your relationship with those treating you. You will still be offered all available care 1394 that suits your needs and medical condition. 1395

1396

Who can I call if I have questions or problems? 1397 For questions about the study or a research-related injury, contact Institution Name. You will be given a copy of this consent form to keep. 1398 Principal Investigator: Name – Telephone xx xxxx xxxx; 1399 Co Investigators: Name – Telephone xx xxxx xxxx; 1400

1401 Who has reviewed this study? 1402 This study has been reviewed and approved by the Institutional Human Research Ethics Committee. Should you wish to discuss the study with 1403 someone not directly involved, in particular in relation to matters concerning policies, information about the conduct of the study or your rights as 1404 a participant, or should you wish to make a independent complaint, you can contact the Institutional Human Research Ethics Committee + 1405 Contact Details. 1406

1407 1408 1409


- Confidential -


HOSPITAL OR INSTITUITION NAME 1410 PATIENT CONSENT FORM 1411

1412


1415

PRINCIPAL INVESTIGATOR: Name 1416 1417

I, …………………………………………… herewith declare that I fully understand the purpose and the implications of the study on the treatment 1418 of endometrial carcinoma. 1419 I understand that; 1420

a) The aim of the study is to develop the best treatment for endometrial carcinoma, 1421 b) The study will not have any immediate benefits for myself, 1422 c) Participation involves surgery, 1423 d) The information obtained will be collected in a potentially identifiable, but de-identified fashion and will be used only in relation to 1424

Medical Research, 1425 e) By signing this document I give permission for access to my medical records, for the purpose of this research, 1426 f) I can withdraw from the study at any time. 1427

I have read and understood the information sheet and I have had an opportunity to ask questions. I am satisfied with the answers given. I 1428 consent to participate in this research. 1429 1430 1431 Signature of Research Participant Signature of Witness 1432 1433 1434 Name of Research Participant Name of Witness 1435 1436 1437

Date Date 1438 1439 1440 Signature of Investigator 1441 1442 1443 Name of Investigator Date 1444

1445

1446

APPENDIX 4: DEMOGRAPHICS FORM1447


LACE: Statistical Analysis Plan Protocol: Version 6 – May 2009

Page 48 of 96

1448

1449

1450



Page 49 of 96

APPENDIX 5: FACT G 1451 1452

1453



Page 50 of 96

1454 1455



Page 51 of 96

APPENDIX 6: EURO-QOL 5D 1456

1457



Page 52 of 96

1458 1459



Page 53 of 96

APPENDIX 7: HEALTH SERVICES QUESTIONNIARE 1460

1461 1462



Page 54 of 96

APPENDIX 8: PELVIC FLOOR DISTRESS INVENTORY 1463 1464 1465

1466



Page 55 of 96

1467 1468

1469



Page 56 of 96

Appendix 9: LACE Stage 1 Summary 1470

1471

LACE Stage 1 Summary

Primary Objective Comparison of Quality of Life (QoL) at 6 months post-operatively between patients who receive TAH versus patients who receive TLH.

Primary Hypothesis The primary hypothesis was that Total Laparoscopic Hysterectomy (TLH) is associated with equivalent or improved Quality of Life (QoL) at 6 months when compared to the standard treatment of Total Abdominal Hysterectomy (TAH) for women with Stage 1 endometrial cancer.

Sample Size 180 patients using 2:1 randomisation, with 120 patients randomised to receive TLH and 60 patients randomised to receive TAH.

The fist stage was randomised design to detect a minimum 8-point improvement in the FACT-En QoL scale at 6-months post-op.

Primary Outcome Quality of Life: Change in quality of life: Functional Assessment of Cancer Therapy – Endometrium (FACT-En) between baseline (pre-surgery) and 6 months after surgery.

Duration of Study Enrolment for Stage 1 was completed within the projected 2 year period. Study Stage 1 was considered complete when 180 patients were enrolled and had completed 6 months follow-up with respect to Quality of Life.

Design The Stage 1 design was conducted as a Phase III international, multi-centre, open-label, randomised clinical trial, assessing the Quality of Life at 6 months post-operatively of Total Laparoscopic Hysterectomy surgery against Total Abdominal Hysterectomy surgery.

1472

1473

1474 1475



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LACE: 1476

LAPAROSCOPIC APPROACH TO CARCINOMA OF THE 1477

ENDOMETRIUM 1478

1479

An international, multicentre, randomised, phase III 1480

clinical trial 1481

1482 1483

Statistical Analysis Plan 1484 1485

Version 1: 13th January 2016 1486 1487 1488

1489

Principal Investigator: A/Prof Andreas Obermair, Queensland Centre for Gynaecological Cancer

Sponsor: Queensland Centre for Gynaecological Cancer

Collaborators: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Tyco Healthcare Group Gynetech Queensland Government - Smart Health Research Grant National Health and Medical Research Council, Australia Cancer Council Queensland Cancer Council New South Wales Cancer Council Victoria Cancer Council Western Australia Cancer Australia

Coordinating Centre: Queensland Centre for Gynaecological Cancer

Statistician: Professor Val Gebski, NHMRC Clinical Trials Centre

Prepared by: Rebecca Asher, Lucy Davies, Val Gebski NHMRC Clinical Trials Centre

1490 1491

1492

1493

1494



Page 58 of 96

Contents 1495 1 Introduction and Overview ..................................................................................................................................60 1496

1.1 Study Overview ..................................................................................................................... 60 1497

Study Flow Diagram ...................................................................................................... 60 1.1.11498

Primary Objective .......................................................................................................... 60 1.1.21499

Subject Population ........................................................................................................ 60 1.1.31500

Inclusion Criteria ........................................................................................................... 60 1.1.41501

Exclusion Criteria ........................................................................................................... 61 1.1.51502

Randomisation .............................................................................................................. 61 1.1.61503

Study Design .................................................................................................................. 62 1.1.71504

Study Treatments .......................................................................................................... 62 1.1.81505

1.2 Definition of Study Endpoints ............................................................................................... 62 1506

Primary Endpoint .......................................................................................................... 62 1.2.11507

Secondary Endpoints .................................................................................................... 62 1.2.21508 2 Statistical Analysis ....................................................................................................................................................63 1509

2.1 Analysis Overview ................................................................................................................. 63 1510

Trial Size ........................................................................................................................ 63 2.1.11511

Primary Analysis ............................................................................................................ 64 2.1.21512

Description of Available Data ........................................................................................ 65 2.1.31513

2.2 Eligibility Criteria and Patient Status ..................................................................................... 66 1514

2.3 Stratification Balance ............................................................................................................ 67 1515

2.4 Baseline ................................................................................................................................. 68 1516

2.5 Surgery .................................................................................................................................. 69 1517

2.6 Histopathology ...................................................................................................................... 71 1518

2.7 Serious Adverse Events ......................................................................................................... 76 1519

2.8 Efficacy – Disease Evaluation ................................................................................................ 76 1520

2.9 Primary Endpoint: Disease-Free Survival .............................................................................. 77 1521

2.10 Secondary Endpoints ............................................................................................................ 78 1522

Treatment-Related Morbidity ....................................................................................... 78 2.10.11523

Patterns of Recurrence ................................................................................................. 93 2.10.21524

Overall Survival ............................................................................................................. 94 2.10.31525

Quality of Life ................................................................................................................ 95 2.10.41526

2.11 Exploratory Analyses ............................................................................................................. 96 1527

1528



Page 59 of 96

1529

Table 1: Ineligible patients and reason ................................................................................................. 66 1530 Table 2: Patients who did not receive protocol surgery ....................................................................... 66 1531 Table 3: Patients whose attempted protocol surgery was abandoned ................................................ 66 1532 Table 4: Patient record status by treatment arm ................................................................................. 66 1533 Table 5: Stratification variables ............................................................................................................ 67 1534 Table 6: Baseline variables .................................................................................................................... 68 1535 Table 7: Details of protocol surgery ...................................................................................................... 69 1536 Table 8: Pathology, cytopathology and lymph node details ................................................................. 71 1537 Table 9: Serious Adverse Events (SAEs) ................................................................................................ 76 1538 Table 10: Efficacy - Disease Evaluation ................................................................................................. 76 1539 Table 11: On Study Treatment .............................................................................................................. 77 1540 Table 12: Primary Endpoint .................................................................................................................. 78 1541 Table 13: Test for non-inferiority .......................................................................................................... 78 1542 Table 14: Test for superiority ................................................................................................................ 78 1543 Table 15: Intra-operative complications ............................................................................................... 79 1544 Table 16: Worst symptom grade reached at one week post-surgery .................................................. 79 1545 Table 17: Worst overall peri-operative complication grade reached at one week post-surgery ......... 83 1546 Table 18: Worst symptom grade reached at 4-6 weeks post-surgery .................................................. 83 1547 Table 19: Worst overall early post-operative complication grade reached at 4-6 weeks post-surgery1548 .............................................................................................................................................................. 87 1549 Table 20: Worst symptom grade reached at 6 months post-surgery ................................................... 87 1550 Table 21: Worst overall late post-operative complication grade reached at 6 months post-surgery . 91 1551 Table 22: Estimated blood loss ............................................................................................................ 92 1552 Table 23:Post-operative pain and analgesic consumption results ....................................................... 92 1553 Table 24: Localisation of first recurrence ............................................................................................. 93 1554 Table 25: Time to first recurrence by relapse site ................................................................................ 93 1555 Table 26: Overall survival at 4.5 years post-surgery ............................................................................. 94 1556 Table 27: Quality of life measures including EQ-5D, HADS, Pelvic Floor and Body Image Scale .......... 95 1557 Table 28: Exploratory analyses of prognostic factors ........................................................................... 96 1558 1559

Figure 1: KM Plot - Disease-free survival by relapse site ...................................................................... 93 1560 Figure 2: KM Plot - Overall survival by treatment group ...................................................................... 94 1561 1562



Page 60 of 96

1 Introduction and Overview 1563

1.1 Study Overview 1564

Study Flow Diagram 1.1.11565

1566

Primary Objective 1.1.21567

To determine whether Total Laparoscopic Hysterectomy (TLH) surgery is non-inferior to Total 1568 Abdominal Hysterectomy (TAH) surgery, based on disease-free survival at 4.5 years post-surgery. 1569

1570

Subject Population 1.1.31571

The target population for this trial is consenting female patients diagnosed with clinical stage 1 1572 endometrioid adenocarcinoma of the endometrium. 1573

1574

Inclusion Criteria 1.1.41575

Patients who may be included for this study must have the following: 1576



Page 61 of 96

1. Histologically confirmed primary endometrioid adenocarcinoma of the endometrium; 1577

2. Clinically stage I disease; 1578

3. Performance status of ECOG 0-1; 1579

4. Signed written informed consent; 1580 5. Females, aged 18 years or older. 1581

1582

Exclusion Criteria 1.1.51583

Patients were excluded from participating from the study if they have any of the following: 1584

1. Other histologic type than endometrioid adenocarcinoma of the endometrium; 1585 2. Clinically advanced disease (stages II-IV); 1586 3. Uterine size larger than 10 weeks gestation; 1587 4. Estimated life expectancy of less than 6 months; 1588 5. Enlarged aortic lymph nodes; 1589 6. Unfit for surgery: serious concomitant systemic disorders incompatible with the study (at 1590

the discretion of the investigator); 1591 7. Patient compliance and geographic proximity that allow adequate follow-up; 1592 8. Unfit to complete Quality of Life measurements. 1593

1594

Randomisation 1.1.61595

All eligible patients are required to provide signed consent before being randomised. Prior to 1596 randomisation, each patient was screened for eligibility according to the inclusion and exclusion 1597 criteria. The randomisation list will not be available to the study centre, statisticians, or the project 1598 team at QCGC. A web-based computer randomisation procedure will be co-ordinated centrally by 1599 the School of Population Health, University of Queensland, Brisbane, Australia. 1600

Stage 1: Randomised permuted blocks were used to allocate patients between the two treatment 1601 groups with an allocation ratio of 2:1, favouring the intervention of TLH (mixed blocks of sizes 3 and 1602 6). Randomisations were stratified according to treating centre and by grade of differentiation (as 1603 taken from the endometrial biopsy/D&C). 1604

Stage 2: Permuted blocks were used to allocate patients between the two treatment groups with an 1605 allocation ratio of 1:1. Randomisations were stratified according to treating centre, grade of 1606 differentiation and history of malignancy. By the end of Stage II accrual, there will be approximately 1607 55 more participants allocated to TLH as a result of 2:1 randomisation in Stage I of the trial. 1608

1609



Page 62 of 96

Study Design 1.1.71610

The study will be conducted as a Phase III international, multicentre, open-label, randomised clinical 1611 trial, assessing disease-free survival at 4.5 years post-operatively of Total Laparoscopic Hysterectomy 1612 (TLH) versus Total Abdominal Hysterectomy (TAH). 1613

1614

Study Treatments 1.1.81615

• Standard treatment: Total Abdominal Hysterectomy (TAH) + pelvic/aortic lymph node 1616 dissection. 1617

• Experimental treatment: Total Laparoscopic Hysterectomy (TLH) + laparoscopic pelvic/aortic 1618 lymph node dissection. 1619

1620

1.2 Definition of Study Endpoints 1621

Primary Endpoint 1.2.11622

The primary endpoint is disease-free survival at 4.5 years post-surgery, as measured by the time 1623 interval between surgery and date of first recurrence or death. Presence of recurrent disease will be 1624 proven by clinical assessment, radiological work-up ± histological confirmation. 1625

1626

Secondary Endpoints 1.2.21627

1. Treatment-related morbidity as evaluated by: 1628 a. Intraoperative complications: injury to bladder, ureter, bowel; vascular injury and 1629

bleeding, nerve injury; 1630 b. Perioperative complications: urinary tract infection, urinary retention, ileus, cardiac 1631

(myocardial infarction, atrial fibrillation), pulmonary (oedema, atelectasis, 1632 pneumonia), renal and cerebrovascular morbidity. Wound and vault complications 1633 (infection, breakdown, and dehiscence), septicaemia and thromboembolic 1634 complications (DVT, PE), lymphocyst or abscess formation; 1635

c. Early postoperative complications: Wound and vault complications (infection, 1636 dehiscence). Lymphocyst, abscess formation, lymphoedema or fistula formation; 1637

d. Long-term post-operative complications: Lymphoedema, incisional hernia 1638 formation. 1639

e. Estimated blood loss: Haemoglobin change from baseline. A Full Blood Count 1640 (haemoglobin) will be taken before surgery and the morning after; 1641

f. Postoperative pain and analgesic consumption; 1642 1643

2. Local control: Endometrial-specific time to recurrence is defined in months as the time 1644 interval from randomisation until evidence of the first site of progression is in the 1645 endometrium. First site of progression outside the endometrium or death from any cause 1646



Page 63 of 96

will be considered as a competing risk. Those patients who discontinue treatment for 1647 reasons other than progression in the endometrium and are not competing risks will be 1648 censored at the time of discontinuation. Endometrial-specific time to progression will be 1649 described using cumulative incidence curves for all ITT patients and the corresponding 1650 median time to progression times and 95% confidence limits will be provided. 1651 1652

3. Quality of Life - this will be assessed using the following questionnaires: 1653

a. EuroQoL-5d (EQ-5D): a standardised instrument for use as a measure of health 1654 outcome, it provides a descriptive profile and a single index value for health status. 1655 EQ-5D was originally designed to complement SF-36. EQ-5D will measure changes in 1656 health status and quality of life to calculate the quality-adjusted life years (QALYs) 1657 gained with the intervention. 1658

b. Pelvic Floor Distress Inventory: measures symptom severity and quality of life 1659 changes in women with pelvic floor disorders. The Pelvic Floor Distress Inventory 1660 (PFDI) provides a standardised, reproducible assessment of the patient’s symptoms 1661 and their effect on daily life. 1662

c. Psychological functioning: specifically measuring anxiety and depression using the 1663 Hospital Anxiety and Depression Scale (HADS). This is a screening instrument which 1664 was specifically developed to measure anxiety and depression in physically ill 1665 patients through omission of items measuring common physical features of such 1666 diagnoses. The HADS will be administered by qualified study staff at Visits 1, 3, 4, 5 1667 and 6. 1668

d. Body Image Scale (BIS): a 10-item scale developed by the European Organization 1669 for Research and Treatment of Cancer (EORTC) Quality of Life Study Group 1670 measuring body image concerns of cancer patients. The BIS will be administered by 1671 qualified study staff at Visits 1, 3, 4, 5 and 6. 1672

4. Patterns of recurrence: date and localisation of first recurrence; 1673

5. Overall survival at 4.5 years post-surgery. Time to death will be calculated from 1674 randomisation. Patients who are known to still be alive at 4.5 years post-surgery or are lost 1675 to follow up will be censored at date last known to be alive. 1676 1677 1678

2 Statistical Analysis 1679

2.1 Analysis Overview 1680

Trial Size 2.1.11681

The final sample size for Stage II has been determined to require 755 patients (405 TLH versus 350 1682 TAH patients). For the Stage I design of this trial (assessing equivalence in QoL outcomes), a 2:1 1683 randomisation scheme was used to maximise the data collected on the TLH patients if the trial did 1684 not progress to Stage II. This provided 180 patients by the completion of Stage I (120 allocated to 1685 TLH, 60 allocated to TAH). As Stage II progressed from Stage I, a sample size of 640 patients was 1686 originally targeted using a randomisation ratio of 0.76:1 for intervention: control in order to 1687



Page 64 of 96

minimise the imbalance (would result in 370 TLH versus 270 TAH). However, this strategy was soon 1688 deemed unfeasible for surgeons due to recruitment problems. As a result, the randomisation ratio 1689 was set to 1:1 for the remainder of the Stage II recruitment period. 1690

Given this, the final sample size for the study was determined to require 755 patients to declare non-1691 inferiority between the two surgical procedures with respect to the proportion surviving at 4.5 years. 1692

This sample size assumes a final randomisation ratio of 0.86:1 (350 in TAH versus 405 in TLH) with 1693 90% power, based on 60 months of patient accrual, 54 months of follow-up and a 5% Type I error. 1694 The sample size calculations were conducted by the trial statisticians at the NHMRC Clinical Trials 1695 Centre using ACCoRD software. 1696

1697

Power Accrual Time (months)

Follow-up Time (months)

Randomisation ratio

Total Sample Size TLH Group TAH Group

87% 54 54 0.76 730 415 315

85% 54 54 0.86 705 380 325

90% 54 54 0.86 775 415 360

90% 60 54 0.86 755 405 350

90% 60 60 0.86 705 380 325

Based on these numbers, for a 5-year accrual and a 4.5 year follow-up, a total of 755 patients would 1698 be sufficient to declare non-inferiority with a non-inferiority margin of 7% or less at 4.5 years. 1699 1700

Primary Analysis 2.1.21701

The primary analysis will be according to the intention-to-treat (ITT) principal. A secondary analysis 1702 of the primary outcome will be performed according to surgery received. 1703

Non-inferiority will be declared if the lower bound of the one-sided 97.5% CI for the difference in 1704 disease-free survival at 4.5 years post-surgery is ≥-7%. The disease free survival proportion will be 1705 estimated from the Kaplan-Meier curve. 1706

Continuous variables will be summarised in terms of means and standard deviation (SD) where 1707 appropriate or median (range), categorical variables will be presented as frequency (percentage). 1708 For continuous variables, differences between randomisation groups will be assessed using 1709 appropriate tests (such as a t-test) and where normality assumptions are not met appropriate 1710 transformations of the data may be applied or other strategies (use of categories and/or non-1711 parametric tests) may be employed. Difference between groups with respect to categorical 1712 variables will be evaluated using the chi-squared or an appropriate exact test. 1713

Analysis of disease-free survival, overall survival and other time to event endpoints will be analysed 1714 using the log-rank test and proportional hazards regression, and displayed using the method of 1715 Kaplan-Meier. Exploratory analyses adjusting for pre-specified prognostic factors including age, BMI, 1716 stage, grade of differentiation, lymph node involvement, history of malignancy, and ECOG status will 1717



Page 65 of 96

be performed using proportional hazards regression methods. Subgroup analyses will be performed 1718 using logistic regression including a test for interaction between subgroup and treatment. 1719

P values for statistical tests will be presented with 95% CIs where appropriate. 1720

1721

Description of Available Data 2.1.31722

1723 The completeness index C, which quantifies the effect of losses to follow-up or commencement of 1724 other anti-cancer therapy, will be reported: 1725 1726

C=100 x (total observed follow-up time)/(total potential follow-up time) 1727 1728 where a participant’s potential follow-up is the time from their entry into the study to the cut-off 1729 date for the study closure or the date of the event if it has occurred. 1730 1731 A measure of the maturity of the data will also be calculated: median follow-up time will be 1732 calculated using the reverse Kaplan-Meier method with time of censoring as the outcome rather 1733 than death and death being treated as censored. Minimum and maximum follow-up time will also be 1734 reported. 1735 1736 1737

1738

1739

1740

1741

1742

1743

There may be missing values in some of the prognostic factors used in the regression analysis of 1744 primary and secondary outcomes. Percentage of missing values will be reported and methods for 1745 dealing with any missing data will be described in the relevant sections. 1746

Follow-up time calculated with reverse Kaplan Meier (censored values treated as events and events 1747 censored) 1748 1749 1750

Completeness and maturity of survival data

Total (N= 75?)

Completeness (%)

Median follow-up time

Minimum follow-up time

Maximum follow-up time



Page 66 of 96

2.2 Eligibility Criteria and Patient Status 1751

The eligibility criteria for all patients has been summarised in the tables below. 1752

Table 1: Ineligible patients and reason 1753

Site Patient Randomised treatment

Reason

1754

Table 2: Patients who did not receive protocol surgery 1755


Reason

1756

Table 3: Patients whose attempted protocol surgery was abandoned 1757


Reason

1758

Table 4: Patient record status by treatment arm 1759

Total Abdominal Hysterectomy

N= N(%)

Total Laparoscopic Hysterectomy

N= N(%)

Total

N= N(%)

Patients randomised

No protocol surgery received

Attempted surgery not completed

Ineligible

Lost to follow-up at 4.5 years

1760

1761



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2.3 Stratification Balance 1762

Randomisation was stratified according to treating centre, grade of differentiation and history of 1763 malignancy. 1764

Table 5: Stratification variables 1765

Stratification variable Total Abdominal Hysterectomy

N(%)


N (%)

Total N (%)

Hospital Box Hill

Christchurch Women’s Hospital

Greenslopes Private Hospital

John Hunter Hospital

King Edward Memorial Hospital

Mater Hospital

Monash Medical Centre

Queen Mary Hospital

Royal Brisbane and Women’s

Hospital

Royal Adelaide Hospital

Royal Infirmary of Edinburgh

Royal Women’s Hospital

St John of God Hospital

Sunshine Coast Hospital

Wesley Hospital

Westmead Hospital

Grade of Differentiation:

1

2

3

History of Malignancy

No

Yes

1766

1767

1768



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2.4 Baseline 1769

Baseline variables have been summarised by treatment group as mean (SD) or frequency 1770 (percentage) depending on normality and data type. 1771

Table 6: Baseline variables 1772


N=


N= Total N=

N(%) or Mean(SD) N(%) or Mean(SD) N(%) or Mean(SD)

Demographics:

Age at randomisation: Years

Weight: kg

Height: cm

Disease evaluation:

Did patient have chest X-ray?

Result

Yes

Abnormal

Did patient have CT Abdomen?

Result

Yes

Abnormal

Did patient have CT Pelvis?

Result

Yes

Abnormal

Did patient have US Abdomen?

Result

Yes

Abnormal

Did patient have US Pelvis?

Result

Yes

Abnormal

Did patient have ECG?

Result

Yes

Abnormal

Did patient have MRI?

Result

Yes

Abnormal

Did patient have hysterectomy D&C?

Result

Yes

Abnormal

Concomitant:

Medical Conditions

Inactive

Mild

Moderate

Severe

Life-threatening

Missing



Page 69 of 96


N=


N= Total N=

N(%) or Mean(SD) N(%) or Mean(SD) N(%) or Mean(SD)

Sign or Symptom None

Mild

Moderate

Severe

Life-threatening

Medication Ongoing

ECOG Performance Status: 0

1

1773

1774

2.5 Surgery 1775

Surgical variables have been summarised as mean (SD)/median (range) or frequency (percentage) 1776 depending on normality and data type. Differences between treatment groups will be assessed using 1777 an appropriate test for continuous variables and a Chi-squared test for discrete. 1778

1779

Table 7: Details of protocol surgery 1780


N= N(%) or

Mean(SD)/Median (Range)


N= N(%) or


Total N=

N(%) or Mean(SD)/Medi

an (Range)

p-value

Surgery Details

Days to surgery (from randomisation): days

Length of operation (scalpel to stitch): minutes

Pelvic/Aortic Lymph Node Dissection? Yes

Macroscopic LN Involvement? No

Para-aortic

Pelvic

Para-aortic and Pelvic



Page 70 of 96


N= N(%) or



N= N(%) or


Total N=


an (Range)

p-value

Other Procedure? No

USO

BSO

Other

Teaching Case? Yes

Total Abdominal Hysterectomy details (n=)

TAH completed? No

Type of Laparotomy Incision: Vertical Midline

Lower Transverse

Total Laparoscopic Hysterectomy details (n=)

TLH Completed? No

Type of Pneumoperitoneum? Hasson

Verres Needle:

Umbilical

Suprapubic

Palmer’s Point

Number of ports:

Number of ports ≥10mm:

Uterine artery secured laparoscopically?

Yes

Vaginal vault closed laparoscopically?

Yes

Laparoscopy converted to laparotomy>

No

Complications



Page 71 of 96


N= N(%) or



N= N(%) or


Total N=


an (Range)

p-value

Anatomical reason

Unacceptable long operating times

Technical reasons

1781

1782

2.6 Histopathology 1783

Histopathology variables have been summarised as mean (SD)/median (range) or frequency 1784 (percentage) depending on normality and data type. Differences between treatment groups have 1785 been assessed using the appropriate test for continuous variables and a Chi-squared test for 1786 discrete. 1787

Table 8: Pathology, cytopathology and lymph node details 1788


N= N(%) or



N= N(%) or


Total N=


an (Range)

p-value

Pathology Details

Histological Type: ICD-01a

ICD-01b

ICD-02a

ICD-02b

ICD-03a

ICD-03b

Surgical Stage: 1a

1b

2



Page 72 of 96


N= N(%) or



N= N(%) or


Total N=


an (Range)

p-value

3a

3b

3c1

3c2

4a

4b

Missing

Histological Grade: Not Stated

1

2

3

Missing

Nuclear Grade: Not stated

Uniform, small nucleoli

More variability, large nucleoli

Pleomorphic, macro nucleoli

Not applicable

Myometrium Width: mm

Myometrium Invasion: mm

Lymphatic Invasion: Not stated

No invasion

Invasion identified

Suspicious

Vascular Invasion: Not stated

No invasion



Page 73 of 96


N= N(%) or



N= N(%) or


Total N=


an (Range)

p-value

Invasion identified

Suspicious

Cervical Involvement: Not stated

No invasion

Surface invasion

Stromal invasion

Vaginal Involvement: Not stated

No invasion

Invasion identified

Extrauterine Extension: Not stated

No extension

Extension identified

Resection Margin: Not stated

Clear

Involved

Omentum: Not submitted

Clear

Involved

Cytopathology

Cytology Result: Negative

Positive

Suspicious

Not done

Lymph Nodes

Para-aortic:

Submitted Yes



Page 74 of 96


N= N(%) or



N= N(%) or


Total N=


an (Range)

p-value

Number received

Number metastatic

Obturator Left:

Submitted Yes

Number received

Number metastatic

Obturator Right:

Submitted Yes

Number received

Number metastatic

External Illiac Left:

Submitted Yes

Number received

Number metastatic

External Illiac Right:

Submitted Yes

Number received

Number metastatic

Common Illiac Left:

Submitted Yes

Number received

Number metastatic

Common Illiac Right:

Submitted Yes

Number received

Number metastatic

Pelvic Left:

Submitted Yes



Page 75 of 96


N= N(%) or



N= N(%) or


Total N=


an (Range)

p-value

Number received

Number metastatic

Pelvic Right:

Submitted Yes

Number received

Number metastatic

Pelvic Unknown:

Submitted Yes

Number received

Number metastatic

1789

1790

1791



Page 76 of 96

2.7 Serious Adverse Events 1792

SAEs are reported by treatment received and differences assessed using a Chi-squared test. 1793

Table 9: Serious Adverse Events (SAEs) 1794

Total Abdominal

Hysterectomy N=

N(%)


N= N(%)

Total N=

N(%)

p-value

Number of SAEs reported*

#

Causality Related to surgery

Unrelated to surgery

Unknown

Severity Mild

Moderate

Severe

Life-threatening

*These numbers are not mutually exclusive, i.e. some patients had more than one SAE 1795

1796

2.8 Efficacy – Disease Evaluation 1797

The management of patients with recurrent disease is summarised below in terms of frequency 1798 (percentage) and by treatment arm. 1799

Table 10: Efficacy - Disease Evaluation 1800

Total Abdominal

Hysterectomy N=

N(%)


N= N(%)

Total N=

N(%)

p-value

Number of relapses: #

Radiotherapy: Yes

Chemotherapy: Yes

1801

1802



Page 77 of 96

Table 11: On Study Treatment 1803

Total Abdominal

Hysterectomy N(%)


N(%)

Total N(%)

Chemotherapy Details: Drug

Adriamycin Number of patients: Number cycles:

Carboplatin Number of patients: Number cycles:

Cisplatin Number of patients: Number cycles:

Etoposide Number of patients: Number cycles:

Epirubicin Number of patients: Number cycles:

Paclitaxel Number of patients: Number cycles:

Provera Number of patients: Number cycles:

Taxol Number of patients: Number cycles: Reason for Ceasing Completed Treatment Toxicity Death Patient Request Intercurrent Illness Other Radiotherapy Details: External Beam Whole Pelvis Number of patients:

Fractions Median(range) Dose Median(range)

External Beam Para-aortic Number of patients: Fractions Median(range)

Dose Median(range) Brachytherapy/Vaginal Vault Boost

Number of patients

Fractions Median(range) Dose Median(range)

Reason for ceasing Completed Treatment Other Missing 1804

2.9 Primary Endpoint: Disease-Free Survival 1805

The primary end point is disease-free survival at 4.5 years post-surgery as measured by the time 1806 interval between date of surgery and date of first recurrence. Presence of recurrent disease is 1807 proven by clinical assessment, radiological work-up ± histological confirmation. 1808



Page 78 of 96

The survival probability for each treatment group at 4.5 years post-surgery and their difference will 1809 be calculated using the Kaplan-Meier estimate of the survival functions and presented alongside the 1810 95% CI. Non-inferiority will be declared if the lower bound of the one-sided 97.5% CI for the 1811 difference between survival probabilities is ≥-7%. 1812

A closed testing procedure for superiority will also be performed. 1813

Table 12: Primary Endpoint 1814

All patients N(%)


N(%)


% (95% CI)

Disease-free survival at 4.5 years post-surgery:

1815 1816

Table 13: Test for non-inferiority 1817

All patients N(%)

Difference between

treatment groups N(%)

97.5% one-sided CI for difference

Non-inferiority p-value


1818

1819

Table 14: Test for superiority 1820

All patients N(%)

Difference between

treatment groups N(%)

Superiority p-value


1821

2.10 Secondary Endpoints 1822

Treatment-Related Morbidity 2.10.11823

The following tables report the worst complication level experienced intra-, peri- and post-1824 operatively. All analyses of complications are per treatment received, summarised as frequency 1825 (percentage) and differences between treatment groups assessed using a Chi-squared test. 1826



Page 79 of 96

1827

2.10.1.1 Intra-Operative Complications 1828

Table 15: Intra-operative complications 1829


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Bladdery: Yes

Blood Transfusion: Yes

Bowel Injury: Yes

Nerve Injury: Yes

Ureter Injury: Yes

Uterus Rupture: Yes

Vaginal Laceration: Yes

Vascular Injury: Yes

1830

2.10.1.2 Peri-Operative Complications: one week post-surgery 1831

Table 16: Worst symptom grade reached at one week post-surgery 1832


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Abdominal Abscess: Not present

Mild

Moderate

Severe

Life-Threatening

Cardiac: Not present

Mild

Moderate

Severe

Life-Threatening

Cerebrovascular: Not present



Page 80 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Mild

Moderate

Severe

Life-Threatening

Chest Infection: Not present

Mild

Moderate

Severe

Life-Threatening

DVT: Not present

Mild

Moderate

Severe

Life-Threatening

GI Fistula: Not present

Mild

Moderate

Severe

Life-Threatening

GI Ileus > 7days: Not present

Mild

Moderate

Severe

Life-Threatening

Hernia: Not present

Mild

Moderate

Severe

Life-Threatening

Lymphoedema: Not present

Mild



Page 81 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Moderate

Severe

Life-Threatening

Pelvic Abscess: Not present

Mild

Moderate

Severe

Life-Threatening

Post-operative Haemorrhage:

Not present

Mild

Moderate

Severe

Life-Threatening

Pulmonary: Not present

Mild

Moderate

Severe

Life-Threatening

Pulmonary Embolus: Not present

Mild

Moderate

Severe

Life-Threatening

Renal: Not present

Mild

Moderate

Severe

Life-Threatening

Return to theatre same admission:

Not present

Mild



Page 82 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Moderate

Severe

Life-Threatening

Septicaemia: Not present

Mild

Moderate

Severe

Life-Threatening

Urinary Fistula: Not present

Mild

Moderate

Severe

Life-Threatening

UTI: Not present

Mild

Moderate

Severe

Life-Threatening

Vault Haematoma: Not present

Mild

Moderate

Severe

Life-Threatening

Wound Dehiscence: Not present

Mild

Moderate

Severe

Life-Threatening

Wound Infection: Not present

Mild



Page 83 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Moderate

Severe

Life-Threatening

Other No

Yes

1833

1834

Table 17: Worst overall peri-operative complication grade reached at one week post-surgery 1835

Worst Grade Encountered


N= N(%)


N= N(%)

Total N=

N(%)

p-value

0 – Not present

1 - Mild

2 - Moderate

3 - Severe

4 - Life threatening

1836

2.10.1.3 Early Post-Operative Complications: 4-6 weeks post-surgery 1837

Table 18: Worst symptom grade reached at 4-6 weeks post-surgery 1838


N= N(%)


N= N(%)

Total N=

N(%)

p-value


Mild

Moderate

Severe

Life-Threatening




Page 84 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening

DVT: Not present

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening

Hernia: Not present

Mild



Page 85 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Not present

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening

Renal: Not present

Mild



Page 86 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Moderate

Severe

Life-Threatening


Not present

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening

UTI: Not present

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild



Page 87 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening

Other No

Yes

1839

Table 19: Worst overall early post-operative complication grade reached at 4-6 weeks post-surgery 1840



N= N(%)


N= N(%)

Total N=

N(%)

p-value

0 – Not present

1 - Mild

2 - Moderate

3 - Severe


1841

1842

1843

1844

2.10.1.4 Late Post-Operative Complications: 6 months post-surgery 1845

Table 20: Worst symptom grade reached at 6 months post-surgery 1846



Page 88 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening

DVT: Not present

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening




Page 89 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Mild

Moderate

Severe

Life-Threatening

Hernia: Not present

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Not present

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening




Page 90 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Mild

Moderate

Severe

Life-Threatening

Renal: Not present

Mild

Moderate

Severe

Life-Threatening


Not present

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening

UTI: Not present

Mild

Moderate

Severe

Life-Threatening




Page 91 of 96


N= N(%)


N= N(%)

Total N=

N(%)

p-value

Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening


Mild

Moderate

Severe

Life-Threatening

Other No

Yes

1847

Table 21: Worst overall late post-operative complication grade reached at 6 months post-surgery 1848



N= N(%)


N= N(%)

Total N=

N(%)

p-value

0 – Not present

1 - Mild

2 - Moderate

3 - Severe


1849



Page 92 of 96

2.10.1.5 Estimated Blood Loss 1850

Blood loss is calculated as the Haemoglobin change from baseline. Levels will be summarised as 1851 mean (SD) or median (IQR) depending on normality and the difference between groups assessed 1852 using regression analysis, adjusting for baseline value. 1853

Table 22: Estimated blood loss 1854


N= Mean (SD) or

Median (Range)


N= Mean (SD) or

Median (Range)

Total N=

Mean (SD) or Median (Range)

p-value

Haemoglobin Level G/L

Prior to surgery:

Morning after surgery:

Change:

1855

1856

2.10.1.6 Post-Operative Pain & Analgesic Consumption 1857

Post-operative pain was measured on a scale of 1-10 and summarised as median (range) for each 1858 treatment group. Difference between the treatment groups will be assessed using the Mann-1859 Whitney test. The number of patients consuming analgesic medication will be summarised as 1860 frequency (percentage) and compared between treatments using a Chi-squared test. 1861

1862

Table 23:Post-operative pain and analgesic consumption results 1863


N=


N= Total N= p-value

Pain score Median (range)

Analgesic consumption:

N (%)

1864

1865



Page 93 of 96

Patterns of Recurrence 2.10.21866

Localisation of first recurrence has been summarised as frequency (percentage) and compared 1867 between groups using a Chi-squared test. Median disease-free survival times have been summarised 1868 using the method of Kaplan and Meier and survival curves have been compared between relapse 1869 sites using the Log-rank test. 1870

Figure 1: KM Plot - Disease-free survival by relapse site 1871

1872

Table 24: Localisation of first recurrence 1873

Total Abdominal

Hysterectomy N=

N(%)


N= N(%)

Total N=

N(%)

p-value

Recurrent Disease: Yes

Site of Relapse: Vault

Pelvis

Abdomen

Distant

Multiple

Port Site

Other

1874

Table 25: Time to first recurrence by relapse site 1875

Total Abdominal

Hysterectomy N=

Median (IQR)


N= Median (IQR)

Total N=

Median (IQR)

p-value

Site of Relapse: Vault

Pelvis

Abdomen

Distant

Multiple

Port Site

Other



Page 94 of 96

1876

1877

1878

1879

1880

Overall Survival 2.10.31881

Overall survival as measured from date of surgery to the date of death by any cause. Cause of death 1882 has been summarised as frequency (percentage) and compared between groups using the Chi-1883 squared test. Median survival times have been summarised using the method of Kaplan and Meier 1884 and the survival curves have been compared between groups using the Log-rank test. 1885

Figure 2: KM Plot - Overall survival by treatment group 1886

1887

Table 26: Overall survival at 4.5 years post-surgery 1888

Total Abdominal

Hysterectomy N=

N(%)


N= N(%)

Total N=

N(%) or HR (95% CI)

p-value

Death: Yes

Cause of Death: Unknown

Endometrial Cancer

Intra-Operative Complication

Peri-Operative Complication

Post-Operative Complication

Unrelated Morbidity

Other

Time to Death: Median (IQR)

1889

1890

1891



Page 95 of 96

Quality of Life 2.10.41892

Quality of life scores have been summarised as median (range) for each time point by treatment 1893 group and compared using regression analysis, adjusting for baseline value. 1894

Table 27: Quality of life measures including EQ-5D, HADS, Pelvic Floor and Body Image Scale 1895


N= Median(Range)


N= Median (Range)

Total N=

Median (range) p-value

Visit 1:

HADS Anxiety

Depression

EQ-5D:

Pelvic Floor Distress Inventory:

Body Image Scale

Visit 3:

HADS Anxiety

Depression

EQ-5D:


Body Image Scale

Visit 4:

HADS Anxiety

Depression

EQ-5D:


Body Image Scale

Visit 5:

HADS Anxiety

Depression

EQ-5D:


Body Image Scale

Visit 6:



Page 96 of 96

HADS Anxiety

Depression

EQ-5D:


Body Image Scale

1896

1897

2.11 Exploratory Analyses 1898

Exploratory analyses of potential prognostic factors including age, tumour size, stage, grade of 1899 differentiation, depth of myometrial invasion, lymph node involvement, ECOG status and baseline 1900 quality of life scores was performed using a multivariable Cox regression model. 1901

Table 28: Exploratory analyses of prognostic factors 1902

Hazard Ratio Lower 95% CI Upper 95% CI p-value

Treatment:

TLH vs TAH

Age (years):

BMI (≥30 vs <30):

Surgical Stage:

2 (vs 1)

3/4 (vs 1)

Stage of Differentiation:

2 (vs 1) 3 (vs 1)

Node dissection yes (vs no)

ECOG Status:

1 vs 0

History of malignancy (yes vs no)

1903

1904

1905


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