Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscleinvasive bladder cancer. N Engl J Med 2012;366:

2 Web Supplement WEB SUPPLEMENT 1 COLLABORATORS 1 STUDY OVERSIGHT 2 ACKNOWLEDGEMENTS 3 LENT/SOM 4 RTOG TOXICITY GRADING SYSTEM 7 TABLE 1 - FULL VERSION FOR APPENDIX 7 TABLE 2 - FULL VERSION FOR APPENDIX 12 FIGURE 1 KAPLAN- MEIER PLOT OF (A) DISEASE- FREE SURVIVAL (DFS), (B) METASTASIS FREE SURVIVAL (MFS) 16 Collaborators The following clinicians entered patients into the trial: R. Huddart, RMH Sutton (46); B. Sizer, Essex County (34); N. James, QE Birmingham (22); T. Sreenivasan, Lincoln County (18); D. Bloomfield, Royal Sussex / Worthing Hospital (14); A. Lydon, Torbay Hospital (14); J. Wallace, Beatson Onc Centre (12); F. Adab, University Hospital N.Staffs (11); P. Crellin, Dorset County / Poole Hospital (11); H. Newman, Bristol Oncology Centre / Royal United, Bath (10); D. Sheehan, Royal Devon and Exeter (10); I. Syndikus, Clatterbridge Centre / Warrington Hospital (10); S. Gibbs, Oldchurch (9); A. Stockdale, Walsgrave Hospital (9); C. Elwell, Northampton Hospital (8); J. Graham, Beatson Oncology Centre / Bristol Oncology Centre (8); F. Neave, North Middlesex (8); A. Samanci, New Cross (8); S. Beesley, Kent Oncology Centre (7); P. Hoskin, Mount Vernon (7); A. Cook, Cheltenham Hospital (5); M. Russell, Beatson Oncology Centre (5); J. Glaholm, Goodhope Hospital (4); P. Jenkins, Cheltenham Hospital (4); S. Mangar, Page 1 of 17

3 Hammersmith Hospital (4); N. Srihari, Royal Shrewsbury (4);R. Srinivasan, Royal Devon and Exeter / Torbay Hospital (4); A. Bahl, Royal United, Bath (3); A. Birtle, Royal Preston (3); M. Carr, Princess Royal (3);C. Humber, Warwickshire (3); D. Landau, Guy's & Thomas' (3); T. Roberts, Northern Centre for Cancer Treatment, Newcastle General (3); D. Stewart, Belvoir Park Hospital (3); J. Bowen, Cheltenham Hospital (2); J. Harney, Belvoir Park Hospital (2); F. McKinna, Eastbourne Hospital / Royal Sussex (2); M. Panades, Lincoln County (2);R. Subramanian, King George / Oldchurch (2); H. Taylor, Kent Oncology Centre (2); P. Wells, Homerton / Whipps Cross (2); P. Wilson, Bristol Oncology Centre (2); N. Anyameme, Mount Vernon (1); R. Beard, Worthing Hospital (1); P. Chakraborti, Derbyshire Royal infirmary (1); M. Churn, New Cross (1); J. Davies, Poole Hospital (1); R. Eakin, Belvoir Park Hospital (1); C. Eswar, Southport Hospital (1); T. Hickish, Royal Bournemouth (1); N. Hodson, Royal Sussex (1); P. Leone, Broomfield Hospital (1); J. Littler, Clatterbridge Centre (1); J. O'Sullivan, Belvoir Park Hospital (1); L. Reinecke, Walsgrave Hospital (1); A. Robinson, Royal Sussex (1); C. Rowland, Royal Devon and Exeter (1); H. Van der Voet, James Cook (1); A. Zarkar, Birmingham Heartlands (1). Study Oversight The trial was sponsored by The University of Birmingham and conducted in accordance with the principles of Good Clinical Practice with appropriate ethical and regulatory approvals. Central data management was performed by CRUK Cancer Trials Unit, Birmingham and ICR- CTSU. Statistical monitoring and analyses were conducted at ICR- CTSU. The Trial Management Group (TMG) Page 2 of 17

4 designed and were responsible for running the trial and writing the paper and vouch for the accuracy of the data. The trial was overseen by independent Trial Steering (TSC) and Data Monitoring Committees (DMC). A formal interim safety analysis occurred at 1 year. No adjustments for interim looks at efficacy were planned or made. The decision to submit the manuscript for publication was made jointly by the trial committees. There are no confidentiality agreements in place nor do the authors have any conflicts of interest to declare. The drugs were purchased and no commercial support was sought or received. The TMG designed the study and its members also served as the writing committee and take responsibility for the accuracy and completeness of the data. The decision to submit the manuscript for publication was made jointly by the TMG, DMC and TSC. Acknowledgements BC2001 (Current Controlled Trials number, ISRCTN [controlled- trials.com]) was supported by Cancer Research UK, trial reference number CRUK/01/004 with programme grants to support the work of the CR UK Cancer Trials Unit, Birmingham (C547/A2606; C547/A6845; C9764/A9904) and ICR- CTSU (C1491/A9895)). Trial recruitment was facilitated within centers by the National Institute for Health Research (NIHR) funded National Cancer Research Network. We would like to acknowledge James Morden for additional statistical work carried out prior to publication. Page 3 of 17

5 LENT/SOM Two toxicity systems were used in the trial Radiation Therapy Oncology Group (RTOG) and Late Effects of Normal Tissue (Subjective, Objective, Management) (LENT/SOM). Both are widely used in oncology and are validated. The LENT/SOM is completed by the assessing clinician and is a composite scale that incorporates both the reported toxicity and management used to control a given side effect. It has a number of domains corresponding to various organs at risk, selected according to the site being irradiated. The RTOG scale is simpler as shown below and is also clinician assessed. Both were used in order to get the maximum chance of detecting significant late effects. It should be noted that sexual dysfunction is assessed in LENT/SOM but not the RTOG scale. As this is common in the age group being evaluated, even without treatment for bladder cancer, the LENT/SOM system will demonstrate more late toxicity than the RTOG. Page 4 of 17

6 Lent Som Gradings Rectum Grade 1 Grade 2 Grade 3 Grade 4 Subjective Stool frequency 2-4 per day 5-8 per day >8 per day Uncontrolled Diarrhoea Sphincter control Occasional Intermittent Persistent Refractory Pain Occasional & minimal Intermittent & tolerable Persistent & intense Refractory & excruciating Tenesmus Occasional urgency Intermittent urgency Persistent urgency Refractory Mucosal loss Occasional Intermittent Persistent Refractory Objective Bleeding Occult Occasional >2/week Persistent/daily Gross Haemorage Stricture >2/3 normal diameter with dilatation 1/3-2/3 normal diameter with < 1/3 normal diameter Complete obstruction dilation Ulceration Superficial <= 1cm 2 Superficial > 1cm 2 Deep ulcer Perforation, fistulae Management Pain Occasional non-narcotic Regular non-narcotic Regular narcotic Surgical intervention Tenismus and Occasional, <= 2 Regular, > 2 antidiarrhoeals/week Multiple, <= 2 antidiarrhoeals/day Surgical intervention / stool frequency antidiarrhoeals/week permanent colostomy Bleeding Stool softener, iron therapy Occasional transfusion Frequent transfusions Surgical intervention / permanent colostomy Stricture Diet modification Occasional dilatation Regular dilatation Surgical intervention / permanent colostomy Ulceration Diet modification, stool softener Occasional steriods Steroids per enema, hyperbaric Surgical intervention / oxygen permanent colostomy Sphincter control Occasional use of incontinence pads Intermittent use of incontinence pads Persistent use of incontinence pads Surgical intervention / permanent colostomy Bladder / Urethra Grade 1 Grade 2 Grade 3 Grade 4 Subjective Dysuria Occasional & minimal Intermittent & tolerable Persistent & intense Refractor & excruciating Frequency 3-4 hour intervals 2-3 hour intervals 1-2 hour intervals Hourly Haematuria Occasional Intermittent Persistent with clot Refractory Incontinence < weekly episodes < daily episodes < 2 pads / undergarments / day Refractory Decreased stream Occasionally weak Intermittent Persistent but incomplete obstruction Complete obstruction Objective Haematuria Microscopic, normal haemoglobin Intermittent macroscopic, <10% Persistent macroscopic, 10% - 20% Refractory, > 20% decrease in haemoglobin decrease in haemoglobin decrease in haemoglobin Endoscopy Patchy atrophy or Telangiectasia Confluent atrophy or Telangiectasia Ulcerations into muscle Perforation, fistula without bleeding with gross bleeding Maximum volume >300 cc cc >200 cc cc >100 cc cc < 100 cc Residual volume 25 cc >25 cc cc > 100 cc Management Dysuria Occasional non-narcotic Regular non-narcotic Regular narcotic Surgical intervention Frequency Alkalisation Occasional anti-spasmodic Regular narcotic Cystectomy Haematuria/ Iron therapy Occasional transfusion or single Frequent transfusion or coagulation Surgical intervention Telangiectasia cauterisation Incontinence Occasional use of incontinence pads Intermittent use of incontinence pads Regular use of pad or selfcatheterisation Permanent catheter Decreased stream < Once-a-day self-catheterisation Dilatation, > once-a-day self Permanent catheter, catheterisation surgical intervention Ureter Grade 1 Grade 2 Grade 3 Grade 4 Subjective Pain Occasional & minimal Intermittent & tolerable Persistent & intense Refractory & excruciating Objective Obstruction Ureteral narrowing without Ureteral narrowing with Unilateral obstruction Bilateral obstruction hydronephrosis hydronephrosis Renal function 1+ proteinuria 2+ proteinuria 4+ proteinuria Management Pain Occasional non-narcotic Regular non-narcotic Regular narcotic Surgical intervention Obstruction Unilateral stent or nephrostomy Bilateral nephrostomy or diversion Male Sexual Dysfunction Grade 1 Grade 2 Grade 3 Grade 4 Subjective Erectile function for Occasionally insufficient Intermittently insufficient Not sufficient Impotent vaginal penetration Dryness Occasional Intermittent Persistent Refractory Desire Occasional Intermittent Seldom Never Satisfaction Occasional Intermittent Seldom Never Objective Frequency Decreased from normal Rare Never Orgasm Occasional Intermittent Seldom Never Management Impotence Medical intervention Surgical intervention Page 5 of 17

7 Female Sexual Dysfunction Grade 1 Grade 2 Grade 3 Grade 4 Subjective Dyspareunia Occasional Intermittent Persistent Refractory Dryness Occasional Intermittent Persistent Refractory Desire Occasional Intermittent Seldom Never Satisfaction Occasional Intermittent Seldom Never Objective Vaginal stenosis / >2/3 normal length 1/3-2/3 normal length <1/3 normal length Obliteration length Synechiae Partial Complete Frequency Decreased from normal Rare Never Orgasm Occasional Intermittent Seldom Never Management Dryness Hormone replacement Artificial lubrication Stenosis / Occasional dilation Intermittent dilation Persistent dilation Surgical reconstruction Synechiae Dyspareunia Occasional hormone cream Intermittent hormone cream Persistent hormone cream Small Intestine / Colon Grade 1 Grade 2 Grade 3 Grade 4 Subjective Stool frequency 2-4 per day 5-8 per day >8 per day Refractory Diarrhoea Stool consistency Bulky Loose Mucous, dark, watery Pain Occasional & minimal Intermittent & tolerable Persistent & intense Refractory / Rebound Constipation 3-4 per week Only 2 per week Only 1 per week No stool in 10 days Objective Melena Occult/Occasional Intermittent & tolerable, normal Hb Persistent, 10-20% decrease in Hb Refractory or frank blood > 20% decrease in Hb!! Weight loss from >=5% - 10% >10% - 20% >20% - 30% >30% time of treatment Stricture >2/3 normal diameter with dilatation 1/3-2/3 normal diameter with dilation < 1/3 normal diameter Complete obstruction Ulceration Superficial <= 1cm 2 Superficial > 1cm 2 Deep ulcer Perforation, fistulae Management Pain Occasional non-narcotic Regular non-narcotic Regular narcotic Surgical intervention Stool consistency / frequency Diet modification Regular use of non-narcotic antidarrhoea Continuous use of narcotic antidiarrhoea Bleeding Iron therapy Occasional transfusion Frequent transfusions Surgical intervention Stricture Occasional diet adaptation Diet adaptation required Medical intervention, NG suction Surgical intervention Ulceration Medical intervention Surgical intervention Skin / Subcutaneous Tissue Grade 1 Grade 2 Grade 3 Grade 4 Subjective Scaliness / Present / asymptomatic Symptomatic Require constant attention Roughness Sensation Hypersensitivity, pruritus Intermittent pain Persistent pain Debilitating dysfunction Objective Oedema Present / asymptomatic Symptomatic Secondary dysfunction Total dysfunction Alopecia (scalp) Thinning Patchy, permanent Complete, permanent Pigmentation Transitory, slight Permanent, marked change Ulcer / Necrosis Epidermal only Dermal Subcutaneous Bone exposed Telangiectasia Minor Moderate <50% Gross >50% Fibrosis / Scar Present / asymptomatic Symptomatic Secondary dysfunction Total dysfunction Atrophy / Contraction (depression) Management Dryness Present / asymptomatic Symptomatic / <10% Secondary dysfunction / 10% - 30% Total dysfunction / >30% Medical intervention Sensation Intermittent medical intervention Continuous medical intervention Ulcer Medical intervention Surgical intervention / amputation Oedema Medical intervention Surgical intervention / amputation Fibrosis / Scar Medical intervention Surgical intervention / amputation Mature bone (Excluding Mandible) Grade 1 Grade 2 Grade 3 Grade 4 Subjective Pain Occasional & minimal Intermittent & tolerable Persistent & intense Refractory & excruciating Function Interferes with athletic recreation Interferes with work Interferes with daily activity Complete lack of function Joint movement Stiffness interfering with athletic recreation Stiffness interfering with work Stiffness interfering with daily activity Complete fixation, necrosis Objective Fracture Partial thickness Full thickness Mucosa soft tissue Sequestration Skin over bone Erythema Ulcer Sinus Fistula Joint movement <10% decrease >10% - 30% decrease >30% - 80% decrease >80% decrease Management Pain Occasional non-narcotic Regular non-narcotic Regular narcotic Surgical intervention Function Occasional physiotherapy Intermittent physiotherapy Persistent physiotherapy or medical Surgical intervention intervention Joint movement Occasional physiotherapy Intensive physiotherapy Corrective surgery Page 6 of 17

8 RTOG Toxicity Grading system RTOG Gradings for Late Side Effects After Radiotherapy No symptoms Minor symptoms requiring no treatment Symptoms responding to simple out patient management, lifestyle (performance status) not affected Distressing symptoms altering the patient s lifestyle (performance status) Hospitalisation for diagnosis or minor surgical intervention (such as urethral dilation) may be required Major surgical intervention (such as laparotomy colostomy, cystectomy) or prolonged hospitalisation required Fatal complications Table 1 - Full version for Appendix Chemo- RT RT Total N % N % N % Page 7 of 17

9 Total % % % RT randomization Standard RT % % % Reduced high dose volume RT % % % Elect standard RT % % % Sex Male % % % Female % % % WHO Performance Status % % % % % % % 6 3.4% % Age at randomization (63.7, Median (IQR) 72.3 (65.1, 76.6) ) 71.9 (64.1, 76.2) < % % % % % % % % % % % % Pathological stage - primary tumor % 1* 0.6% 1 0.3% % % % 3a % % % Page 8 of 17

10 3b % % % 4a 7 3.8% 7 3.9% % Unknown 0 0.0% 1 0.6% 1 0.3% Grade primary tumor % 0 0.0% 1 0.3% % % % % % % Unknown 1 0.5% 3 1.7% 4 1.1% Histological type TCC % % % SCC 2 1.1% 0 0.0% 2 0.6% Adenocarcinoma 1 0.5% 0 0.0% 1 0.3% Other 2 1.1% 2 1.1% 4 1.1% Unknown 0 0.0% 1 0.6% 1 0.3% Multiple tumors Yes % % % If yes, number of tumors Median (IQR) 3 (2, 4) 3 (2, 4) 3 (2, 4) Number unknown No % % % Unknown 0 0.0% 3 1.7% 3 0.8% Tumor resection² Not resected 5 2.7% 4 2.2% 9 2.5% Page 9 of 17

11 Biopsy % 9 5.1% % Complete Resection % % % Incomplete Resection % % % Resected (extent unknown) 1 0.5% 1 0.6% 2 0.6% Unknown 3 1.6% 2 1.1% 5 1.4% Residual mass post resection ² Yes % % % No % % % Unknown % 9 5.1% % Tumor size (longest dimension, mm) Median (IQR) 30 (21, 47) 30 (25, 50) 30 (25, 50) Unknown Neoadjuvant CT planned Yes % % % No % % % Planned Radiotherapy schedule 55Gy/20F % % % 64Gy/32F % % % Unknown 0 0.0% 1 0.6% 1 0.3% Abbreviations in table 1: IQR = interquartile range. TCC= transitional cell carcinoma; SCC = squamous cell carcinoma. CT= chemotherapy. Page 10 of 17

12 Footnotes to table 1: * The tumor was only staged as T1 pathologically but radiological staging confirmed the tumor as T3. Therefore the patient was not considered ineligible for the trial 1 anaplastic small cell carcinoma (ineligible), 1 TCC & SCC 1 TCC & SCC, 1 TCC & adenocarcinoma ² Findings from pre- radiotherapy cystoscopy but may have been after primary debulking or neoadjuvant chemotherapy and hence not always the first cystoscopy for the disease. Page 11 of 17

13 Table 2 - Full version for Appendix Worst grade of toxicity for CTC (on-treatment) and RTOG & LENT/SOM (at 1 year, 2 years and over all follow-up visits from 6 months to 5 years after randomization). P- values are from Mantel-Haenszel Chi-square test (odds ratio) of proportion at grade 3-4 and Van Elteren test (median & IQR) of distribution of grades. Chemo- RT Odds ratio Worst grade (N=178) RT (N=182) (95% CI) P- value N(%) with data % % Acute - All Grade % % CTC Grade % % (0.96, 2.38) Median (IQR) 2 (2, 3) 2 (1, 3) N(%) with data % % Genito- Grade % % urinary Grade % % (0.60, 1.66) Median (IQR) 1.5 (1, 2) 1 (1, 2) 0.50 N(%) with data % % Gastro- Grade % % Page 12 of 17

14 intestinal Grade % 5 2.7% (1.35, 10.93) Median (IQR) 1 (1, 2) 1 (0, 1) < N(%) with data % % Late - At 1 year Grade % % RTOG Grade % 1 1.3% (0.30, 27.90) Median (IQR) 0 (0, 0) 0 (0, 0) 0.20 N(%) with data % % At 2 years Grade % % Grade % 3 5.2% (0.19, 4.39) Median (IQR) 0 (0, 0) 0 (0, 0) 0.94 N(%) with data % % Over all Grade % % follow- up Grade % % (0.21, 1.10) Median (IQR) 0 (0, 1) 0 (0, 1) 0.55 Page 13 of 17

15 N(%) with data % % Late - At 1 year Grade % % LENT/SOM Grade % % (0.72, 2.81) Median (IQR) 1 (0, 3) 1 (0, 3) 0.57 N(%) with data % % At 2 years Grade % % Grade % % (0.44, 2.01) Median (IQR) 2 (0, 3) 1 (0, 3) 0.93 N(%) with data % % Over all Grade % % follow- up Grade % % (0.64, 1.90) Median (IQR) 3 (1, 4) 3 (1, 4) 0.99 Abbreviations in table: IQR = interquartile range CI = confidence interval Page 14 of 17

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17 Figure 1 Kaplan- Meier plot of (a) Disease- free Survival (DFS), (b) Metastasis Free Survival (MFS) (a) Proportion disease-free HR (95% CI) = 0.78 ( ) Stratified logrank p= Months since randomization N at risk (events) Chemo-RT 182 (62) 108 (23) 76 (4) 66 (2) 56 (1) 46 (3) 25 RT 178 (73) 96 (22) 69 (10) 58 (3) 44 (2) 35 (3) 18 (b) Page 16 of 17

18 Proportion metastasis-free HR (95% CI) = 0.72 ( ) Stratified logrank p= Months since randomization N at risk (events) Chemo-RT 182 (42) 128 (17) 101 (8) 86 (2) 71 (0) 58 (2) 34 RT 178 (47) 120 (24) 91 (10) 76 (7) 54 (4) 39 (2) 20 Total number of events (Chemo- RT & RT): DFS 95 & 113, MFS 71 & 94 Cox model estimated absolute difference (95% CI): At 2 years: DFS, 8.6% (- 1.1%, 17.3%), MFS 9.5% (0.4%, 17.0%) At 5 years: DFS, 8.9% (- 1.1%, 18.6%), MFS 11.3% (0.4%, 21.1%). Page 17 of 17