Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Schaapveld M, Aleman BMP, van Eggermond AM, et al. Second cancer risk up to 40 years after treatment for Hodgkin s lymphoma. N Engl J Med 2015;373:2499-511. DOI: 10.1056/NEJMoa1505949
Supplementary Appendix Supplement to: Schaapveld M, Aleman BMP, van Eggermond AM, et al. Second Cancer Risk Up To Forty Years after Treatment for Hodgkin Lymphoma Contents Supplementary methods section on treatment of Hodgkin s Lymphoma in the study cohort not included in main paper. page 2 Supplementary figure S1. Cumulative incidence of subsequent malignant neoplasms (SMN) According to period of diagnosis with death as competing risk (A: lung SMN in males, B: SMN of stomach, pancreas, colon or rectum, C:NHL, D: leukemia, excluding MDS). Solid lines represent the observed incidence, dashed lines the expected incidence in the general population. page 3 Supplementary table S1. Treatment characteristics. page 4 Supplementary table S2. Time-trends in treatment for Hodgkin s lymphoma (primary treatment and treatment for recurrence combined). page 5 Supplementary table S3. Standardized incidence ratios (SIR) and absolute excess risks (AER) for selected subsequent malignant neoplasms (SMN) according to age at 1st treatment for Hodgkin s lymphoma (HL), follow-up duration and attained age. page 6 Supplementary table S4. Multivariable competing risk analysis (death as competing risk) of risk of subsequent malignant neoplasms (SMN) according to treatment period. page 8 Supplementary table S5. Standardized incidence ratios (SIR) and cumulative incidence for selected subsequent malignant neoplasms (SMN) according to radiation fields and estimated cumulative dose of procarbazine. page 10 Supplementary table S6. Multivariable Cox analyses of treatment as risk factor for selected subsequent malignant neoplasms (SMN). page 14 1
Treatment of HL in the study cohort We recorded detailed information on RT fields, chemotherapeutic agents, and number of cycles. Information on radiation doses and fractionation schedules for individual patients was not routinely collected. RT techniques changed over the years. In the early 1960s, patients were treated with cobalt60 or, rarely, with orthovoltage therapy. The number of patients treated with Cobalt-60 only represents a small part of our cohort (approximately 150 patients). Linear accelerators were used (usually 8 MV photons) since the mid-1960s. In the Netherlands the first linear accelerator became operational in 1964 in the Erasmus Medical Center Cancer Institute, Rotterdam. The University Medical Center Utrecht and the Netherlands Cancer Institute followed in 1965 and 1968, respectively. In the other participating centers linear accelerators became available in the early 1970s (Catharina Hospital 1973, the Leiden University Medical Center 1974 and VU University Medical Center Amsterdam 1975). All other centers did not participate in our cohort until the mid-1980s. Individual blocks were used to shield normal tissues as much as possible. In addition, most patients were treated with parallel opposed fields with one field per day until 1990 and two fields per day from 1990 onwards. Patients usually received 40 Gy (36 to 44 Gy) in fractions of 2.0 or 1.8 Gy. Mantle field irradiation was the most commonly applied radiation field from the early 1970s to the late 1980s. Since the late 1980s, a growing number of patients received more limited radiation fields (involved field irradiation). It was not until the late 1990s, however, that elective mantle field after chemotherapy was abandoned. In our cohort, limited supradiaphragmatic radiation fields were applied during all treatment periods. The majority of patients treated with mediastinal irradiation also received supraclavicular/neck irradiation. The nowadays commonly used involved node or involved site radiotherapy had not been introduced yet during the period covered by our study. Patients in our cohort were almost exclusively treated based on 2D treatment planning, 3D conformal planning generally started in the Netherlands with the introduction of involved site/node irradiation. A variety of single and poly-agent chemotherapy regimens were used during the 1960s. The mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) regimen was introduced in our cohort in 1970 and by far the most common combination regimen used until the late 1980s. Other common regimens (mostly used for treatment of recurrences) were lomustine-procarbazine, cyclophosphamide-procarbazine, chlorambucil-procarbazine, and mechlorethamine-lomustine combinations; most of these therapies were given in addition to MOPP or alternated with MOPP. The doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen was introduced in 1982 either alone or alternated with MOPP. A smaller proportion received epirubicin, bleomycin, vinblastine, prednisone (EBVP) combination chemotherapy. From 1990 MOPP/ABV became the standard regimen in our cohort. Although primary treatment was usually given according to treatment protocols of the European Organisation of Research and Treatment of Cancer, treatment for recurrences was generally not standardized. 2
Figure S1 Cumulative incidence of subsequent malignant neoplasms (SMN) according to period of diagnosis with death as competing risk (A: lung SMN in males, B:any SMN of stomach, pancreas, colon or rectum, C:NHL, D: leukemia, excluding MDS). Solid lines represent the observed incidence, dashed lines the expected incidence. A B C D 3
Table S1 Treatment characteristics Radiation fields # No RT 473 12.1 Full mantle field only 815 20.9 Full mantle field + infradiaphragmatic RT 1,176 30.1 Other supradiaphragmatic field only 824 21.1 Other supradiaphragmatic field + infradiaphragmatic RT 219 5.6 Infradiaphragmatic RT only 202 5.2 RT, field unknown 196 5.0 Number of cycles with alkylating chemotherapy #,1,2 No CT 1,068 27.4 CT, non-alkylating 243 6.2 <4 cycles 887 22.7 4-6 cycles 852 21.8 7-9 cycles 290 7.4 >10 cycles 319 8.2 Alkylating CT, number of cycles unknown 16 0.4 CT, unknown if alkylating agents 230 5.9 Procarbazine #1,3 No CT 1,068 27.4 CT without procarbazine 495 12.7 4.2 g/m2 procarbazine 940 24.1 >4.2-8.4 g/m2 procarbazine 745 19.1 >8.4 g/m2 procarbazine 427 10.9 CT, unknown if procarbazine 230 5.9 Splenectomy No 2,466 63.2 Yes 882 22.6 Unknown 557 14.3 Recurrence No 2,976 76.2 Yes, within 5 years after treatment start 724 18.5 Yes, 5 or more years after treatment start 205 5.3 Vital status Alive 2,480 63.5 Dead 1,263 32.4 Emigrated/ lost to follow-up 162 4.1 RT=radiation therapy; CT=chemotherapy; # Treatment data include treatment for recurrence; 1 six cycles of MOPP-ABV hybrid or BEACOPP regimen counted as 3 MOPP equivalent cycles for number of alkylating cycles. One cycle of MOPP contains 1.4 g per square meter of body-surface area (m 2 ) of procarbazine and 12 mg/m 2 of body-surface area of mechlorethamine; one cycle of MOPP/ABV contains 0.7 g/m 2 procarbazine and 6 mg/m 2 mechlorethamine; one cycle of BEACOPP (baseline or escalated) contains 0.7 g/m 2 procarbazine; 2 for 193 patients number of cycles imputed, either for primary or relapse treatment; 3 for 142 patients number of cycles imputed, either for primary or relapse treatment. 4
Table S2 Time-trends in treatment for Hodgkin s lymphoma (primary treatment and treatment for recurrence combined) 1965-1976 1977-1988 1989-2000 N % N % N % Treatment # RT only 271 33.5 387 32.4 410 21.6 CT only 57 7.1 99 8.3 317 16.7 RT & CT 480 59.4 709 59.3 1,175 61.8 Radiation fields # No RT 57 7.1 99 8.3 317 16.7 Full mantle field only 216 26.7 390 32.6 209 11.0 Full mantle field + infradiaphragmatic RT 361 44.7 458 38.3 357 18.8 Other supradiaphragmatic field only 71 8.8 77 6.4 676 35.5 Other supradiaphragmatic field + infradiaphragmatic RT 47 5.8 57 4.8 115 6.1 Infradiaphragmatic RT only 32 4.0 87 7.3 83 4.4 RT, field unknown 24 3.0 27 2.3 145 7.6 Prescribed mediastinal radiation dose; mean (sd) $ Average dose (sd) 38.3 Gy (9.0) 37.0 Gy (7.3) 37.6 Gy (5.1) Procarbazine # No CT 271 33.5 387 32.4 410 21.6 CT without procarbazine 114 14.1 87 7.3 294 15.5 4.2 g/m 2 procarbazine 57 7.1 100 8.2 786 41.2 >4.2-8.4 g/m 2 procarbazine 112 13.9 367 30.7 266 14.0 >8.4 g/m 2 procarbazine 172 21.3 204 17.1 51 2.7 CT, unknown if procarbazine 82 10.2 50 4.2 98 5.2 Number of cycles with alkylating CT # * No CT 271 33.5 387 32.4 410 21.6 CT, non-alkylating 78 9.7 4 0.3 161 8.5 <4 cycles 53 6.6 77 6.4 757 39.8 4-6 cycles 99 12.3 397 33.2 356 18.7 7-9 cycles 76 9.4 132 11.1 82 4.3 >10 cycles 145 18.0 140 11.7 34 1.8 Unknown number of alkylating cycles 4 0.5 8 0.7 4 0.2 CT, unknown if alkylating 82 10.2 50 4.2 98 5.2 Splenectomy No 416 51.5 744 62.3 1306 68.7 Yes 373 46.2 416 34.8 93 4.9 Unknown 19 2.4 35 2.9 503 26.5 RT denotes radiation therapy; CT denotes chemotherapy; sd denotes standard deviation; Gy denotes Gray; # Data include treatment for recurrence; P-value for heterogeneity between treatment periods <0.001 for all variables; *six cycles of MOPP-ABV hybrid or BEACOPP regimen counted as 3 MOPP equivalent cycles for number of alkylating cycles; $ mediastinal dose information was available for 45.2% of the patients who received mediastinal irradiation. 5
Table S3 Standardized incidence ratios (SIR) and absolute excess risks (AER) for selected subsequent malignant neoplasms (SMN) according to age at 1 st treatment for Hodgkin s lymphoma (HL), follow-up duration and attained age Second cancer or cancer site Any SMN Any solid SMN Female breast Lung & Bronchus Gastro-intestinal *1 N SIR (95%CI) AER N SIR (95%CI) AER N SIR (95%CI) AER N SIR (95%CI) AER N SIR (95%CI) AER Sex Male 453 4.5 (4.1-4.9) 112 367 3.9 (3.5-4.4) 85.8 NR NR NR 126 6.7 (5.6-7.9) 32.9 79 3.8 (3.0-4.7) 17.9 Female 431 4.8 (4.4-5.3) 134 390 4.5 (4.1-5.0) 119 183 4.7 (4.0-5.4) 54.3 50 5.8 (4.3-7.7) 15.0 46 3.8 (2.8-5.0) 12.2 P- heterogeneity 0.28 0.038 0.029 0.001 - - 0.43 <0.001 0.95 0.12 Age at 1 st HL treatment 15-24 years 283 8.4 (7.5-9.5) 111 257 8.3 (7.3-9.4) 99.8 94 10.2 (8.3-12.5) 73.3 33 10.3 (7.1-14.5) 12.5 41 9.8 (7.0-13.3) 15.5 25-34 years 292 5.0 (4.4-5.6) 118 249 4.6 (4.0-5.2) 97.7 62 4.4 (3.4-5.6) 54.1 57 7.4 (5.6-9.6) 23.5 34 3.6 (2.5-5.0) 11.7 35-50 years 309 3.1 (2.8-3.5) 144 251 2.6 (2.6-3.0) 105 27 1.7 (1.1-2.5) 18.4 86 5.2 (4.2-6.4) 44.9 50 2.6 (1.9-3.4) 19.9 P- trend <0.001 0.038 <0.001 0.73 <0.001 <0.001 <0.001 <0.001 <0.001 0.65 Follow-up duration 5-9 years 132 4.5 (3.8-5.3) 55.6 89 3.3 (2.7-4.1) 33.6 10 1.6 (0.8-2.9) 4.5 24 7.4 (4.8-11.1) 11.2 11 2.8 (1.4-5.0) 3.8 10-14 years 168 4.3 (3.7-5.0) 83.5 135 3.7 (3.1-4.4) 63.5 28 3.4 (2.2-4.9) 28.0 25 5.2 (3.3-7.6) 12.7 19 3.3 (2.0-5.2) 8.4 15-19 years 200 5.1 (4.4-5.8) 150 180 4.8 (4.1-5.6) 132 47 5.6 (4.1-7.5) 76.8 42 7.7 (5.5-10.3) 32.2 28 4.4 (2.9-6.3) 19.1 20-24 years 146 4.5 (3.8-5.3) 182 136 4.4 (3.7-5.2) 165 32 4.8 (3.3-6.8) 83.0 32 6.4 (4.4-9.0) 38.6 26 4.5 (2.9-6.6) 29.0 25-29 years 122 4.9 (4.1-5.9) 274 111 4.6 (3.8-5.6) 241 38 8.0 (5.7-11.0) 186 25 6.1 (3.9-9.0) 50.2 19 3.8 (2.3-6.0) 34.0 30-34 years 76 4.9 (3.8-6.1) 362 70 4.7 (3.6-5.9) 324 18 6.7 (3.9-10.5) 170 15 5.3 (3.0-8.8) 56.6 14 4.0 (2.2-6.6) 49.3 35 years 40 3.9 (2.8-5.4) 364 36 3.6 (2.5-5.0) 302 10 5.3 (2.5-9.7) 140 13 6.7 (3.5-11.4) 94.6 8 3.0 (1.3-6.0) 47.1 P- trend 0.82 <0.001 0.06 <0.001 <0.001 <0.001 0.64 <0.001 0.68 <0.001 Attained age; 15-24 at HL <30 years 25 11.1 (7.2-16.4) 39.3 18 9.9 (5.8-15.6) 27.9 4 19.8 (5.4-50.6) 12.3 NR NR NR 4 39.6 (10.8-101) 6.7 30-39 years 96 10.3 (8.4-12.6) 84.1 88 10.6 (8.5-13.1) 77.0 31 12.9 (8.8-18.3) 55.3 6 19.5 (7.2-42.4) 5.3 13 19.1 (10.2-32.7) 11.5 40-49 years 98 8.8 (7.1-10.7) 181 96 9.2 (7.5-11.3) 178 37 9.4 (6.6-12.9) 138 13 12.5 (6.6-21.3) 22.8 14 10.8 (5.9-18.1) 24.4 50-59 years 56 6.7 (5.1-8.7) 333 47 5.9 (4.3-7.9) 266 19 8.6 (5.1-13.4) 215 11 8.2 (4.1-14.7) 54.2 8 5.3 (2.3-10.4) 36.9 60 years 8 3.2 (1.4-6.3) 276 8 3.1 (1.4-6.2) 253 3 7.4 (1.5-21.7) 218 3 6.3 (1.3-18.5) 90.2 2 3.4 (0.4-12.2) 51.2 P- trend <0.001 <0.001 <0.001 <0.001 0.06 <0.001 0.05 <0.001 <0.001 0.002 Attained age; 25-34 at HL <40 years 39 6.3 (4.5-8.6) 50.8 28 5.1 (3.4-7.3) 34.7 6 3.7 (1.4-8.1) 15.2 2 7.8 (0.9-28.3) 2.7 5 9.5 (3.1-22.3) 6.9 40-49 years 118 5.9 (4.9-7.1) 111 97 5.3 (4.3-6.4) 88.7 33 5.2 (3.6-7.3) 69.3 17 9.0 (5.2-14.4) 16.4 7 2.9 (1.2-5.9) 5.0 50-59 years 93 4.5 (3.6-5.5) 202 84 4.3 (3.5-5.4) 178 18 4.0 (2.4-6.3) 82.5 25 7.7 (5.0-11.4) 53.5 13 3.5 (1.9-6.1) 23.0 60-69 years 39 3.6 (2.5-4.9) 328 37 3.6 (2.5-4.9) 308 4 2.7 (0.7-6.9) 57.5 13 6.4 (3.4-11.0) 99.8 8 3.2 (1.4-6.3) 50.2 70 years 3 2.5 (0.5-7.2) 310 3 2.5 (0.5-7.4) 306 NR NR NR NR NR NR NR NR NR P- trend 0.001 <0.001 0.025 <0.001 0.39 <0.001 0.41 0.001 0.25 0.039 6
Table S3, continued Attained age; 35-50 at HL <50 years 42 4.1 (2.9-5.5) 75.3 30 3.2 (2.1-4.5) 48.6 4 1.4 (0.4-3.5) 6.4 11 10.0 (5.0-17.8) 23.3 NR NR 50-59 years 144 3.5 (3.0-4.2) 148 115 3.0 (2.5-3.6) 109 13 1.8 (0.9-3.0) 20.1 45 6.9 (5.0-9.2) 52.9 19 2.7 (1.6-4.2) 16.3 60-69 years 93 2.5 (2.0-3.1) 197 76 2.1 (1.7-2.7) 136 7 1.7 (0.7-3.4) 21.1 19 2.8 (1.7-4.4) 37.7 19 2.5 (1.5-3.9) 35.3 70-79 years 27 2.6 (1.7-3.8) 347 27 2.6 (1.7-3.8) 328 3 2.9 (0.6-8.5) 67.8 11 5.5 (2.7-9.8) 142 11 4.0 (2.0-7.2) 133 80 years 3 3.0 (0.6-8.7) 451 3 2.7 (0.6-7.9) 361 NR NR NR NR NR 0.0 (0.0-117) NR P- trend 0.005 <0.001 0.08 <0.001 0.005 0.012 0.003 0.020 0.13 <0.001 The standardized incidence ratio (SIR) and absolute excess risk (AER) for the comparison of the incidence of second cancers observed in the study cohort of Hodgkin s lymphoma survivors with the expected incidence in the general population, with 95% Confidence Intervals (95%CI); NR: not reported ( 1 case observed); *1 data include cancers stomach cancer (C16), pancreatic cancer (C25) and colorectal cancer (C18-C20) 7
Table S4 Multivariable competing risk analysis (death as competing risk) of risk of subsequent malignant neoplasms (SMN) according to treatment period Any SMN Any solid SMN Lung SMN in males Lung SMN in females N shr 95%CI p-value N shr 95%CI p-value N shr 95%CI p-value N shr 95%CI p-value Sex P -heterogeneity <0.001 P -heterogeneity <0.001 Male (ref) 469 1.00 367 1.00 126 na - - Female 439 1.31 1.15-1.49 390 1.52 1.32-1.75 - - 50 na Age P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity 0.044 < 25 (ref) 289 1.00 257 1.00 19 1.00 14 1.00 25-29 162 1.22 1.01-1.46 141 1.18 0.97-1.44 21 2.03 1.11-3.73 3 0.45 0.13-1.51 30-34 134 1.13 0.93-1.38 108 1.01 0.81-1.26 22 2.30 1.27-4.19 11 2.33 1.05-5.20 35-39 115 1.42 1.14-1.76 97 1.32 1.05-1.67 18 2.63 1.40-4.94 9 2.74 1.17-6.37 40-50 208 1.95 1.62-2.34 154 1.51 1.23-1.86 46 4.82 2.85-8.14 13 2.74 1.24-6.06 Period of treatment P -trend 0.015 P -trend 0.63 P -trend 0.001 P -trend 0.14 1965-1976(ref) 337 1.00 275 1.00 53 1.00 15 1.00 1977-1988 360 0.95 0.82-1.10 306 1.02 0.87-1.20 53 0.78 0.53-1.14 19 1.09 0.57-2.06 1989-2000 211 0.79 0.65-0.95 176 0.94 0.77-1.15 20 0.39 0.22-0.69 16 1.76 0.88-3.51 Smoking #1 P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 Never smoker(ref) 297 1.00 248 1.00 13 1.00 6 1.00 Former smoker 267 1.22 1.04-1.44 219 1.25 1.04-1.49 49 2.53 1.36-4.69 15 5.43 2.07-14.2 Recent smoker 180 1.57 1.30-1.88 155 1.66 1.36-2.03 41 4.22 2.26-7.89 16 11.5 4.69-30.1 Unknown 164 0.99 0.81-1.21 135 1.03 0.83-1.28 23 2.41 1.19-4.88 13 4.54 1.78-11.6 8
Table S4, continued Female breast SMN Gastrointestinal SMN* NHL Leukemia/MDS N shr 95%CI p-value N shr 95%CI p-value N shr 95%CI p-value N shr 95%CI p-value Sex P -heterogeneity 0.10 P -heterogeneity 0.043 P -heterogeneity 0.20 Male (ref) - - 79 1.00 69 1.00 44 1.00 Female 183 n.a. 46 0.74 0.51-1.06 33 0.66 0.44-0.99 23 0.72 0.43-1.19 Age P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 < 25 (ref) 94 1.00 41 1.00 24 1.00 16 1.00 25-29 45 1.09 0.74-1.52 22 1.11 0.66-1.86 17 1.41 0.76-2.60 8 1.02 0.43-2.39 30-34 17 0.46 0.28-0.78 12 0.67 0.35-1.26 17 1.76 0.98-3.19 11 1.57 0.73-3.36 35-39 16 0.64 0.38-1.08 12 0.95 0.50-1.80 16 2.12 1.14-3.96 5 1.00 0.36-2.75 40-50 11 0.31 0.16-0.59 38 2.12 1.37-3.27 28 2.58 1.51-4.42 27 3.91 2.10-7.26 Period of treatment P -trend 0.15 P -trend 0.22 P -trend 0.003 P -trend <0.001 1965-1976(ref) 66 1.00 52 1.00 43 1.00 26 1.00 1977-1988 79 1.34 0.96-1.81 44 0.77 0.53-1.13 35 0.63 0.41-0.97 29 0.80 0.47-1.35 1989-2000 38 1.24 0.82-1.87 28 0.79 0.52-1.21 24 0.47 0.28-0.78 11 0.24 0.12-0.49 Smoking #1 Never smoker - - - - - - - - Former smoker - - - - - - - - Recent smoker - - - - - - - - Unknown N denotes the number of SMNs; shr denotes subdistribution hazard ratio; 95%CI denotes 95% Confidence Interval; ref denotes the reference category #1 recent smokers includes current smokers and survivors who quit smoking within 5 years prior to the end follow-up; *: data include cancers stomach cancer (C16), pancreatic cancer (C25) and colorectal cancer (C18-C20) 9
Table S5 Standardized incidence ratios (SIR) and cumulative incidence for selected subsequent malignant neoplasms (SMN) according to radiation fields and estimated cumulative dose of procarbazine N SIR 95%CI p-value CI at 30 years (95%CI) p-value Any SMN * No RT 56 2.1 1.5-2.7 24.7 (19.6-30.2) RT 828 5.1 4.7-5.4 33.9 (31.6-36.3 ) No RT, no procarbazine 4 3.6 1.0-9.2 57.8 (2.7-92.0) No RT, procarbazine 4.2g/m2 9 1.8 0.8-3.5 10.7 (3.1-23.6) No RT, procarbazine >4.2g/m2 38 2.2 1.6-3.1 22.9 (15.9-30.8) RT, no procarbazine 407 4.7 4.2-5.2 35.2 (31.9-38.4) RT & procarbazine 4.2g/m2 115 4.2 3.5-5.0 28.4 (21.3-35.9) RT & procarbazine >4.2g/m2 269 6.3 5.6-7.1 31.8 (28.3-35.4) P- heterogeneity <0.001 0.004 Solid SMN above diaphragm* No RT above diaphragm 33 2.1 1.4-2.9 9.0 (5.7-13.1) RT above diaphragm 409 6.3 5.7-6.9 18.7 (16.8-20.7 ) No RT above diaphragm, no procarbazine 2 0.8 0.1-2.8 3.9 (0.5-13.6) No RT above diaphragm, procarbazine 4.2g/m2 5 2.0 0.6-4.7 3.3 (1.2-7.1) No RT above diaphragm, procarbazine >4.2g/m2 24 2.6 1.7-3.9 11.7 (7.2-17.5) RT above diaphragm, no procarbazine 238 6.8 6.0-7.8 23.1 (20.2-26.2) RT above diaphragm & procarbazine 4.2g/m2 51 4.7 3.5-6.2 12.4 (8.2-17.6) RT above diaphragm & procarbazine >4.2g/m2 111 6.5 5.3-7.8 14.5 (11.8-17.4) Lung & Bronchus: C34 No RT above diaphragm 17 2.7 1.6-4.3 4.6 (2.4-7.8) RT above diaphragm 154 7.7 6.5-9.0 6.8 (5.7-8.1) P- heterogeneity <0.001 0.031 No RT above diaphragm, no procarbazine 1 1.0 0.0-5.3 0.9 (0.1-4.3) No RT above diaphragm, procarbazine 4.2g/m2 3 3.2 0.7-9.4 2.0 (0.5-5.3) No RT above diaphragm, procarbazine >4.2g/m2 12 3.2 1.7-5.6 6.2 (3.0-11.0) RT above diaphragm, no procarbazine 80 7.2 5.7-8.9 7.2 (5.5-9.1) RT above diaphragm & procarbazine 4.2g/m2 23 7.8 5.0-11.8 5.6 (3.1-9.1) RT above diaphragm & procarbazine >4.2g/m2 46 9.0 6.6-12.0 6.5 (4.7-8.7) P- heterogeneity <0.001 0.37 10
Table S5, continued Female breast: C50 No RT above diaphragm 5 1.0 0.3-2.2 3.8 (1.1-9.4) RT above diaphragm 174 5.4 4.6-6.2 18.3 (15.5-21.3) P- heterogeneity <0.001 0.001 No RT above diaphragm, no procarbazine - 0.0 0.0-4.8 0.0 - No RT above diaphragm, procarbazine 4.2g/m2 1 1.2 0.0-6.8 2.3 (0.2-10.6) No RT above diaphragm, procarbazine >4.2g/m2 4 1.3 0.4-3.3 4.8 (1.2-12.5) RT above diaphragm, no procarbazine 118 6.8 5.6-8.2 25.4 (21.0-30.1) RT above diaphragm & procarbazine 4.2g/m2 20 3.6 2.2-5.5 11.2 (5.1-19.9) RT above diaphragm & procarbazine >4.2g/m2 35 4.0 2.8-5.5 9.7 (6.5-13.7) Thyroid: C73 No RT above diaphragm - 0.0 0.0-14.0 0.0 - RT above diaphragm 21 16.0 9.9-24.5 0.9 (0.6-1.4) P- heterogeneity <0.001 - No RT above diaphragm, no procarbazine - 0.0 0.0-78.8 0.0 - No RT above diaphragm, procarbazine 4.2g/m2-0.0 0.0-74.4 0.0 - No RT above diaphragm, procarbazine >4.2g/m2-0.0 0.0-26.7 0.0 - RT above diaphragm, no procarbazine 15 22.3 12.5-36.8 1.3 (0.7-2.2) RT above diaphragm & procarbazine 4.2g/m2 1 3.8 0.1-21.0 0.2 (0.0-1.2) RT above diaphragm & procarbazine >4.2g/m2 4 11.9 3.2-30.4 0.5 (0.2-1.3) P- heterogeneity 0.007 <0.001 Esophagus: C15 No RT above diaphragm 5 5.1 1.6-11.8 2.1 (0.7-5.0) RT above diaphragm 32 11.2 7.7-15.9 1.4 (0.9-2.1) P- heterogeneity 0.10 0.70 No RT above diaphragm, no procarbazine 1 5.9 0.1-32.8 3.1 (0.2-13.4) No RT above diaphragm, procarbazine 4.2g/m2-0.0 0.0-21.1 0.0 - No RT above diaphragm, procarbazine >4.2g/m2 4 7.5 2.1-19.3 2.2 (0.6-5.8) RT above diaphragm, no procarbazine 16 10.4 6.0-16.9 1.4 (0.8-2.4) RT above diaphragm & procarbazine 4.2g/m2 5 10.7 3.5-25.0 0.8 (0.3-1.8) RT above diaphragm & procarbazine >4.2g/m2 9 12.6 5.7-23.9 1.2 (0.5-2.2) P- heterogeneity 0.42 <0.001 11
Table S5, continued Solid SMN below diaphragm** No RT below diaphragm 72 1.7 1.3-2.1 5.5 (4.1-7.2) RT below diaphragm 146 4.6 3.9-5.4 11.5 (9.6-13.7) No RT below diaphragm, no procarbazine 22 1.2 0.8-1.9 3.9 (2.2-6.4) No RT below diaphragm, procarbazine 4.2g/m2 11 1.6 0.8-2.9 9.9 (2.6-23.0) No RT below diaphragm, procarbazine >4.2g/m2 33 2.1 1.5-3.0 6.3 (4.3-9.0) RT below diaphragm, no procarbazine 60 3.5 2.7-4.5 10.5 (7.8-13.8) RT below diaphragm & procarbazine 4.2g/m2 21 4.3 2.6-6.5 10.9 (6.3-16.8) RT below diaphragm & procarbazine >4.2g/m2 55 6.6 4.9-8.5 11.7 (8.7-15.2) Gastrointestinal: C16, C18-20, C25 No RT below diaphragm 34 1.9 1.3-2.6 2.5 (1.6-3.7) RT below diaphragm 85 6.2 5.0-7.7 6.6 (5.1-8.3) No RT below diaphragm, no procarbazine 11 1.5 0.7-2.6 2.1 (1.0-4.1) No RT below diaphragm, procarbazine 4.2g/m2 4 1.5 0.4-3.8 7.9 (1.5-21.6) No RT below diaphragm, procarbazine >4.2g/m2 15 2.3 1.3-3.7 2.4 (1.3-4.1) RT below diaphragm, no procarbazine 28 3.7 2.5-5.4 4.8 (3.0-7.2) RT below diaphragm & procarbazine 4.2g/m2 14 6.9 3.8-11.5 7.9 (3.9-13.7) RT below diaphragm & procarbazine >4.2g/m2 34 9.6 6.7-13.5 7.1 (4.7-10.0) NHL: C82-C88 No RT 6 5.8 2.1-12.6 2.2 (0.8-5.0) RT 98 16.4 13.3-20.0 4.2 (3.3-5.2) P- heterogeneity 0.014 0.11 No RT, no procarbazine 1 25.2 0.6-141 12.5 (0.7-42.3) No RT, procarbazine 4.2g/m2 2 9.3 1.1-33.6 6.0 (0.6-21.2) No RT, procarbazine >4.2g/m2 3 4.9 1.0-14.2 1.4 (0.3-4.6) RT, no procarbazine 47 15.2 11.2-20.3 4.4 (3.1-5.9) RT & procarbazine 4.2g/m2 11 11.1 5.7-19.4 3.9 (1.5-8.3) RT & procarbazine >4.2g/m2 36 23.3 16.3-32.2 4.4 (3.0-6.1) P- heterogeneity 0.016 0.45 12
Table S5, continued Leukemia: C91-C96 No RT 6 10.8 4.0-23.5 1.2 (0.5-2.6) RT 35 10.5 7.3-14.6 1.2 (0.8-1.8) P- heterogeneity 0.95 0.53 No RT, no procarbazine - 0.0 0.0-171 - No RT, procarbazine 4.2g/m2 1 9.1 0.2-50.7 0.7 (0.1-3.7) No RT, procarbazine >4.2g/m2 5 14.9 4.8-34.7 2.1 (0.8-4.5) RT, no procarbazine 8 4.6 2.0-9.1 0.6 (0.2-1.4) RT & procarbazine 4.2g/m2 6 10.6 3.9-23.0 1.0 (0.4-2.2) RT & procarbazine >4.2g/m2 21 24.2 15.0-37.1 2.3 (1.4-3.5) The standardized incidence ratio (SIR) incidence for the comparison of the incidence of second cancers observed in the study cohort of Hodgkin s lymphoma survivors with the expected incidence in the general population and the 30-year cumulative incidence of second cancers, with 95% Confidence Intervals (95%CI). Radiation therapy and dose of procarbazine containing chemotherapy are included as time-varying variables; excludes patients with unspecified radiation therapy field or unknown procarbazine dose; * includes C00-C15, C30-C39, C50, C69-C71, C73; ** includes C16-C26, C51-C68, C74; C75; RT denotes Radiation therapy; N denotes the observed number of second cancers. 13
Table S6 Multivariable Cox analyses of treatment as risk factor for selected subsequent malignant neoplasms (SMN) All solid SMN Lung SMN Breast, female N HR 95%CI p-value N HR 95%CI p-value N HR 95%CI p-value Radiation therapy <0.001 <0.001 <0.001 Full mantle field 530 1.00 117 1.00 159 1.00 Other supradiaphragmatic with axilla 46 0.98 0.71-1.34 15 1.55 0.88-2.71 5 0.36 0.15-0.91 Other supradiaphragmatic fields 72 0.64 0.49-0.83 22 0.88 0.54-1.43 10 0.38 0.19-0.72 RT other & field unknown 65 0.71 0.54-0.92 8 0.28 0.14-0.58 5 0.34 0.14-0.84 No RT 44 0.40 0.29-0.56 14 0.46 0.25-0.83 4 0.26 0.09-0.72 0.001 - - No infradiaphragmatic RT 374 1.00 - - Infradiaphragmatic RT with spleen 201 1.40 1.16-1.68 - - - - - - Other infradiaphragmatic fields 181 1.05 0.87-1.27 - - - - - - - - Number of alkylating cycles 0.33 0.26 0.025 No CT 283 1.00 67 1.00 97 1.00 CT, non-alkylating 48 1.02 0.74-1.40 10 0.63 0.32-1.27 16 1.15 0.67-1.98 <4 cycles 98 1.04 0.82-1.32 25 0.94 0.58-1.53 21 0.74 0.46-1.20 4-6 cycles 165 1.15 0.94-1.40 39 1.03 0.69-1.56 32 0.64 0.42-0.96 7-9 cycles 59 1.21 0.91-1.62 19 1.50 0.87-2.57 5 0.30 0.12-0.73 >10 cycles 61 1.40 1.05-1.87 9 0.73 0.26-1.30 9 0.62 0.31-1.24 CT, unknown if alkylating agents 43 1.06 0.76-1.47 7 0.58 0.26-1.30 3 0.39 0.12-1.24 Smoking <0.001 <0.001 - Never smoker 248 1.00 19 1.00 - - Former smoker 219 1.24 1.03-1.49 64 3.71 2.20-6.24 - - - Recent smoker 155 1.81 1.48-2.23 57 7.74 4.55-13.2 - - - Unknown 135 1.44 1.16-1.80 36 4.64 2.60-8.28 - - - 14
Table S6, continued Gastrointestinal SMN #1 Leukemia/MDS #2 NHL N HR 95%CI p-value N HR 95%CI p-value N HR 95%CI p-value Radiation therapy 0.003 0.76 0.003 Full mantle field 78 1.00 39 1.00 74 1.00 Other supradiaphragmatic with axilla 12 2.16 1.14-4.09 5 1.19 0.46-3.06 9 1.25 0.61-2.57 Other supradiaphragmatic fields 8 0.56 0.26-1.19 9 0.75 0.35-1.60 7 0.32 0.14-0.72 RT other & field unknown 22 1.46 0.89-2.38 6 0.64 0.27-1.55 9 0.58 0.29-1.19 No RT 5 0.37 0.14-0.99 8 0.76 0.31-1.82 6 0.29 0.12-0.71 <0.001 0.09 0.83 No infradiaphragmatic RT 40 1.00 28 1.00 52 1.00 Infradiaphragmatic RT with spleen 42 3.12 1.94-5.01 16 1.63 0.83-3.22 24 0.96 0.57-1.59 Other infradiaphragmatic fields 43 2.27 1.41-3.64 23 2.01 1.06-3.81 29 1.13 0.69-1.83 Number of alkylating cycles <0.001 <0.001 0.015 No CT 30 1.00 11 1.00 34 1.00 CT, non-alkylating 7 1.44 0.61-3.39 - - - 8 1.49 0.69-3.30 <4 cycles 18 2.30 1.26-4.19 6 1.12 0.40-3.12 13 1.12 0.58-2.17 4-6 cycles 30 2.36 1.41-3.96 17 2.81 1.28-6.15 20 1.19 0.68-2.09 7-9 cycles 12 2.86 1.45-5.65 8 3.68 1.44-9.39 14 2.61 1.38-4.95 >10 cycles 12 2.55 1.28-5.09 22 10.8 5.05-23.1 13 2.49 1.28-4.79 CT, unknown if alkylating agents 16 4.65 2.48-8.73 3 1.97 0.53-7.29 3 0.63 0.19-2.09 Splenectomy - 0.65 0.033 No - - 37 1.00 56 1.00 Yes - - - 24 1.25 0.66-2.35 46 1.76 1.09-2.84 Unknown - - - 6 1.40 0.56-3.49 3 0.56 0.17-1.82 Radiation therapy and number of alkylating cycles are included as time-varying variables. P-values are for heterogeneity of hazard ratios. Analysis were adjusted for age and sex and were stratified in the case of non-proportional hazard ratios; RT denotes Radiation therapy; CT denotes chemotherapy; N denotes the observed number of second cancers; HR: hazard ratio; 95%CI: 95% Confidence Interval; #1 data include cancers stomach cancer (C16), pancreatic cancer (C25) and colorectal cancer (C18-C20); #2 data include 24 patients with MDS 15
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