Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Bartelink H, Maingon P, Poortmans P, et al; on behalf of the European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol 2014; published online Dec 9.

2 Online Table A1 Participating centres Participating centres Principal Investigators Number of patients (%) Bernard Verbeeten Instituut, Tilburg, The Netherlands Philip Poortmans, Bin Oei 826 (15.5) Academisch Ziekenhuis Utrecht, The Netherlands H. Struikmans, Carla Rodenhuis 609 (11.5) University Hospital Gasthuisberg, Leuven, Belgium E.Van Limbergen, Caroline Weltens 476 ( 9.0) Centre Georges François Leclerc, Dijon, France JC. Horiot, I Barillot, Philippe Maingon 432 ( 8.1) Institut Curie, Paris, France Alain Fourquet 413 ( 7.8) The Netherlands Cancer Institute, Amsterdam, The Netherlands H. Bartelink, H. Peeterse, C. Vrieling 369 ( 6.9) Radiotherapeutisch Instituut, Heerlen, The Netherlands Jos Jager (now at Maastro Clinic, Maastricht NL) 293 ( 5.5) Radboud University Medical Center, Nijmegen, The Netherlands W. Hoogenraad 264 ( 5.0) Universitaets Klinikum Köln, Germany Rolf Peter Müller 255 ( 4.8) Hopitaux Universitaires de Genêve, Switzerland John Kurtz 184 ( 3.5) Nottingham City Hospital, United Kingdom David Morgan 146 ( 2.7) Institut Regional du Cancer, Montpellier, France Jean-Bernard Dubois 142 ( 2.7) Clinique et maternité Sainte Elisabeth, Namur, Belgium Emile Salamon 120 ( 2.3) Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Rene-Olivier Mirimanoff 107 ( 2.0) Centre Hospitalier Universitaire de Grenoble, Grenoble, France Michel Bolla, 103 ( 1.9) I. Gabelle-Flandin Leiden University Medical Center, Leiden, The Netherlands E. Noordijk, JWH Leer 96 ( 1.8) Centre Hospitalier de Tivoli, La Louvière, Belgium A. Renaud 81 ( 1.5) Rambam University Medical Center, Haïfa, Israel A. Kuten 74 ( 1.4) Staedt Krankenantstalten, Krefeld, Germany U. Schultz 71 ( 1.3) Erasmus Medical Center, Rotterdam, The Netherlands Koper PCM, 49 ( 0.9) Ziekenhuis Network AntwerpenMiddelheim, Antwerpen, Belgium Van den Weyngaert D 47 ( 0.9) Universitair Ziekenhuis Brussel, Belgium Storme GA 46 ( 0.9) Centre Hospitalier Universitaire Henri Mondor, Creteil, France Calitchi GHM 28 ( 0.5) University Hospital Charite, Berlin, Germany Budach V 23 ( 0.4) Heinrich-Heine Universitaetsklinik, Düsseldorf, Germany Roth S, Budach W 17 ( 0.3) Queensland Radium Hospital, Herston-Brisbane, Australia Poulsen M 14 ( 0.3) Hospital de Navarra, Pamplona, Spain Dominguez MA 11 ( 0.2) Centre Saint-Yves, Vannes, France Monpetit E 7 ( 0.1) Hospital Clinic Universitari, Barcelona, Spain Biete Sola A 6 ( 0.1) Tel Aviv Sourasky Medical Center, Tel-Aviv, Israël Kovner F 6 ( 0.1) Hopital General Gregorio Maranon, Madrid, Spain Calvo F 3 ( 0.1) 1

3 Online Table A2: Treatment data Randomized Treatment No Boost (n = 2,638) 16 Gy (n = 2,644) No. of Patients % No. of Patients % WBI Duration, days Median Range Dose range, Gy (point A) > Missing (0.0) Median Range Dose range, Gy (point B) , , > Missing Median Range No. of fractions , , Missing Median Range Radiation quality Cobalt X-ray 1, , Cobalt-60 + X-ray Missing

4 Randomized Treatment No Boost (n = 2,638) No Boost (n = 2,638) Boost received No Boost 2, External , Interstitial External boost Duration external boost, days Median Range External boost dose Median Range Type of boost Electron boost , Cobalt-60 or linear accelerator No. of fractions external boost < , > Maximum fraction dose external boost, Gy , > Interstitial boost Duration of interstitial boost, hours Median Range No. of patients with interstitial boost Interstitial boost dose, Gy Median Range Reference dose rate Median Range Point A is located in the central plane, which is through the centre of the target volume equidistant from the cranial and caudal borders of the fields covering the whole breast. This plane contains the axes of the two tangential beams, which intersect at point A. Point B is located in the tumour plane, which is through the centre of the primary tumour site. This plane will be chosen in the middle of the scar of the tumourectomy, or through the centre of the tumour excision area marked by a clip. The tumour plane contains point B, located in the centre primary tumour excision area; 3

5 Online Table A3. Adjuvant Hormonal or Chemotherapy Treatment No Boost Boost No. of Patients % No. of Patients % Premenopausal, node negative Adjuvant treatment Unknown None Chemotherapy Perioperative and/or concomitant only Adjuvant Premenopausal, node positive Adjuvant treatment Unknown None Chemotherapy Perioperative and/or concomitant only Adjuvant Postmenopausal, node negative 1,301 1,316 Adjuvant treatment Unknown None 1, , Chemotherapy Perioperative and/or concomitant only Adjuvant Tamoxifen Both Perioperative and/or concomitant only Adjuvant Postmenopausal, node positive Adjuvant treatment Unknown None Chemotherapy Perioperative and/or concomitant only Adjuvant Tamoxifen Both Perioperative and/or concomitant only Adjuvant

6 Online Table A4:Site of first local failure (first failure) No Boost (N=354) Boost (N=237) Total (N=591) Primary tumor bed 162 (45.8%) 99 (41.8%) 261 (44.2%) Scar 29 (8.2%) 18 (7.6%) 47 (8.0%) Diffuse 40 (11.3%) 26 (11.0%) 66 (11.2%) Skin outside scar 21 (5.9%) 12 (5.1%) 33 (5.6%) In breast tissue, outside tumor bed 59 (16.7%) 47 (19.8%) 106 (17.9%) Within glandular tissue 17 (4.8%) 9 (3.8%) 26 (4.4%) Unknown 26 ( 7.2%) 26 (11.0%) 52 (8.8%) 5

7 Online table A5 Summary of all events Events during follow-up No Boost 16Gy HR P-value (N=2657) (N=2661) (99% CI) N (%) N (%) Local failure as first event 354 (13.3) 237(8.9) Any Loco-Regional Recurrence 480 (18.1) 352 (13.2) Distant Mets 568 (21.4) 602 (22.6) Any progression 840 (31.6) 788 (29.6) Second Primary Contralateral Breast 208 (7.8) 232 (8.7) 1.12 (1) Second Primary Homolateral Breast 30 (1.1) 21 (0.8) includes angiosarcoma/paget 7 1+1(paget) ( ) Second Primary Non Breast 216 (8.1) 240 (9.0) 1.12 (2) Lung 25 (11.6) 34 (14.2) Skin 39 (18.1) 29 (12.1) Blood 11 (5.1) 17 (7.1) Solid 122 (56.5) 145 (60.4) Unspecified 19 (8.8) 15 (6.3) Death 799 (30.1) 832 (31.3) Cause of death Breast cancer 447 (16.8) 456 (17.1) Second cancer 87 (3.3) 94 (3.5) Infection 13 (0.5) 14 (0.5) Cardiovascular disease 64 (2.4) 68 (2.6) Treatment complications 1 (0.0) 0 (0.0) Other 76 (2.9) 73 (2.7) Unknown 111( 4.2) 127 (4.8) Breast cancer events (Locoregional failure, distant failure, contralateral, death of BC) ( ) 988 (37.2) 940 (35.3) 0.94 (3) ( ) Any event (events in the Disease-free survival endpoint) 1331 (50.1) 1307 (49.1) 0.97 (4) (0.88, 1.08) (1) For calculating the cumulative incidence of contralateral breast cancer the time was defined as the interval in days between the day of randomization and the day of first report of a contralateral breast cancer. Censoring occurred at the time of last visit for all patients who were alive without contralateral breast cancer at their last follow-up. Death without contralateral breast cancer was considered a competing risk in this analysis with the time censored at the day of death (2) For calculating the cumulative incidence of non-breast second cancer, the time was counted as the interval in days between the date of randomization and and the date of report of second cancer located at another site than the breasts, and censored at the time of the last visit for all patients who were alive without non breast second cancer. Death without non breast second cancer was considered a competing risk in this analysis. (3) For computing the cumulative incidence of breast cancer events, time was counted as the interval in days between date of randomization and the date of first report of a breast cancer related event (locoregional relapse, distant metastases of initial cancer, second contralateral or homolateral breast cancer, death related to breast cancer. Patients who had non breast 2 nd cancer or who died of other causes without any of the breast cancer events were analyzed as having a competing event at the time of their first failure. Patients alive without any event were censored at the date of their last follow-up visit. (4) Disease-free survival was counted from date of randomization to the day the first of any type of events (loco-regional, distant, second cancer at any site or death of any cause) was reported. For patients alive without event, censoring occurred at the date of last follow-up visit. 6

8 Online Table A6: Eligibility status Reasons for ineligibility 17 patients on the CR-No boost arm and 10 on the CR-15 Gy boost arm were ineligible. The reasons for ineligibility are as follows: Assigned treatment Classed as Reason for ineligibility Boost Histology benign tumor: D Ashoff Boost Histology PA revision: tumor is a Merkelcel tumor (skin tumor) metastasized to breast Boost microcalcifications microcalicifications op postoperative mammogram, ablatio, no RT given. Boost microcalcifications microcalcifications on postoperative mammogram, RT stopped (26 Gy), ablatio Boost microcalcifications microcalcifications on postoperative mammogram, RT stopped (22 Gy), ablatio Boost Prior malignancy 1 year before randomisation: excision of DCIS in same breast Boost Prior malignancy melanoma in medical history Boost Stage/multifocal tumor multifocal tumour in more than 1 quadrant Boost Stage/multifocal tumor clinical N2 category Boost Stage/multifocal tumor multifocal tumour in more than 1 quadrant No Boost No Boost Histology histology: pure DCIS No Boost Histology histology: pure DCIS surgery not according to the rules, margins biopsy not evaluable No Boost Histology tumour was an intramammary lymph node, ablatio followed, no RT given No Boost Histology histology: pure DCIS No Boost microcalcifications microcalcifications on postoperative mammogram No Boost microcalcifications microcalcifications on postoperative mammogram No Boost microcalcifications postoperative microcalcifications on mammography No Boost microcalcifications microcalcification on mammography postoperatively, ablatio, no RT given No Boost Prior malignancy rectosigmoid carcinoma in 1988 No Boost Prior malignancy coloncarcinoma in 1989 No Boost Prior malignancy ovarium carcinoma in 1988 No Boost Prior malignancy pat. is too old, and has a synchronous malignant tumour in the other breast No Boost Prior malignancy rectal cancer in medical history No Boost Stage/multifocal tumor due to advanced disease: M+ (status changed since past reports) No Boost Stage/multifocal tumor metastases were found before randomisation No Boost Stage/multifocal tumor clinical N2 classification 7

9 Online Figure A1 Trial Design of the boost no boost EORTC Trial 8

10 Online Figure A2: Cumulative incidence of ipsilateral breast tumor recurrence for the whole study population by age. O, occurrences; N, number of patients at risk 9

11 Online figure A3 ipsilateral breast tumor recurrence by age group 10

12 Online figure A4: Cumulative incidence of ipsilateral breast tumor recurrence by type of boost after 50 Gy whole breast irradiation. O, occurrences; N, number of patients at risk 11

13 Online Figure A5: Cumulative incidence of severe fibrosis for the whole population: HR, hazard ratio; O, occurrences; N, number of patients at risk 12

14 Online Figure A6A: Cumulative incidence of first recurrence by treatment arm O, occurrences; N, number of patients at risk 13

15 % recurrence % recurrence % recurrence % recurrence Online Figure A6B: Cumulative incidence of first recurrence by treatment arm by age groups: O, occurrences; N, number of patients at risk No Boost Boost (A) Age 40 yr 15y: 48.1% 41.5% 20y: 56.8% 49.5% O/N 114/228 92/221 HR=0.80 (CI: ) P= (years) No Boost Boost (B) Age yr 15y: 35.6% 34.0% 20y: 44.2% 38.6% HR=0.91 (CI: ) P=0.316 O/N 240/ /669 (years) No Boost Boost (C) Age yr 15y: 28.7% 28.5% 20y: 36.2% 34.7% HR=0.96 (CI: ) P=0.650 O/N 231/ /911 0 (years) No Boost Boost (D) Age >60 yr 15y: 29.1% 27.4% 20y: 32.8% 32.1% HR=0.94 (CI: ) P=0.498 O/N 231/ /911 (years)

16 Online Figure A6C: Cumulative incidence of first recurrence by treatment arm by age groups: Forest plot; HR, hazard ratio; O, occurrences; N, number of patients at risk The endpoint is the time from randomization to first relapse defined as a loco-regional or distant relapse, ipsilateral second cancer or death due to breast cancer. Patients declared to have died of breast cancer without documented relapse were considered has having had distant metastases at the time of death. In this analysis, patients who are diagnosed with a contralateral breast cancer before any other recurrence are censored at the date of the contralateral breast cancer. Patients who die of other causes than breast cancer (including unknown cause) are considered as having a competing event in the analysis. 15

17 Online appendix: Methods and Materials extra information Of the patients with complete resection, were allocated to receive no boost and were allocated to receive a boost. An independent data monitoring committee recommended publication of the local control results in the complete resection group, given that the results after a median of 5 years follow-up revealed a significant clinical impact of this extra radiation dose on the rate of ipsilateral breast cancer recurrence. 2 As specified in the protocol: The initial endpoint of interest is the cosmetic effect within a range of a 5 % difference in local control rate. It is estimated that 90% of the patients treated by standard treatment are free of local recurrence at 10 years. 330 patients should be treated in each treatment arm (a total of 660 for complete patients and 660 for incomplete resection) and followed for 10 years. This number will ensure with 80% probability that the upper 90% confidence limit for the true difference of local recurrence-free rates at 10 years will not exceed 5%, if there is actually no difference in efficacy. After 3 years of recruitment, the recruitment rate was 1000 patients/year. The trial was then amended and the main endpoint was changed: the trial design was revised to incorporate a comparison in terms of overall survival. The sample size was increased in order for the revised protocol to prove a difference of 5% in the 10-year overall survival (from 80% to 85%, HR=0.728 (1.37)) with a power of 90% and a significance level of 1% using a 2-sided logrank test. An independent data monitoring committee recommended publication of the local control results in the complete resection group, given that the results after a median of 5 years follow-up revealed a significant clinical impact of this extra radiation dose on the rate of ipsilateral breast cancer recurrence. 2 At ten years follow up the final results of the trial, according to the primary statistical trial design were presented, they revealed a reduced local recurrence rate in all age groups, however no difference in overall survival was observed. 3 The trial endpoint initially designed to assess the equivalence of the 2 treatment arms within each stratum in terms of local control at 10 years. It was estimated that 660 patients with complete excision and 660 patients with incomplete excision should be treated within the protocol and followed for 10 years in order to ensure a 80% power of testing the equivalence of the 2 treatment within each group with 80% power and a 5% significance level for a 1 sided modified logrank test for equivalence. Equivalence was defined as a decrease by less than 5% from the expected 90% 10-year local control (HR =1.54) Quality Assurance Program An intensive quality assurance program 3-7 was set up to ensure that the treatment was delivered in a standard fashion in all centres. This consisted of a dummy run procedure and on-site visits. Beam calibration in the participating centers was also verified by a team of physicists. Central pathology review was performed by J.L. Peterse at the Netherlands Cancer Institute (Amsterdam, the Netherlands). 16

18 References 1. Poortmans PM, Collette L, Horiot JC, et al. Radiation Oncology and Breast Cancer Groups. Impact of the boost dose of 10 Gy versus 26 Gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10-year results of the randomised EORTC boost trial. Radiother Oncol Jan; 90(1): Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345: Bartelink H, Garavaglia G, Johansson KA, et al. Quality assurance in conservative treatment of early breast cancer: Report on a Consensus Meeting of the EORTC Radiotherapy and Breast Cancer Cooperative Groups and the EUSOMA (European Society of Mastology). Radiother Oncol 1991; 22: van Tienhoven G, Van Bree NAM, MijnheerBJ, et al. Quality assurance of the EORTC trial 22881/10882: Assessment of the role of the booster dose in breast conserving therapy : the Dummy Run. Radiother Oncol 1991; 22: Hamers HP, Johansson KA, Venselaar JLM, et al. Entrance and exit TL-dosimetry in the conservative treatment of breast cancer: A pilot study for the EORTC Radiotherapy Cooperative Group. Radiother Oncol 1991; 22: Heukelom S, Lanson JH, Van Tienhoven G, et al. In vivo dosimetry during tangential breast treatment. Radiother Oncol 1991; 22: Poortmans PM, Ataman F, Davis JB, et al.quality assurance in the EORTC phase III randomised boost vs. no boost trial for breast conserving therapy: Comparison of the results of two individual case reviews performed early and late during the accrual period. Radiother Oncol 2005; 76: