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1 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: DOI: /NEJMoa

2 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

3 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

4 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

5 Table S1 Treatment characteristics Radiation fields # No RT Full mantle field only Full mantle field + infradiaphragmatic RT 1, Other supradiaphragmatic field only Other supradiaphragmatic field + infradiaphragmatic RT Infradiaphragmatic RT only RT, field unknown Number of cycles with alkylating chemotherapy #,1,2 No CT 1, CT, non-alkylating <4 cycles cycles cycles >10 cycles Alkylating CT, number of cycles unknown CT, unknown if alkylating agents Procarbazine #1,3 No CT 1, CT without procarbazine g/m2 procarbazine > g/m2 procarbazine >8.4 g/m2 procarbazine CT, unknown if procarbazine Splenectomy No 2, Yes Unknown Recurrence No 2, Yes, within 5 years after treatment start Yes, 5 or more years after treatment start Vital status Alive 2, Dead 1, Emigrated/ lost to follow-up 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

6 Table S2 Time-trends in treatment for Hodgkin s lymphoma (primary treatment and treatment for recurrence combined) N % N % N % Treatment # RT only CT only RT & CT , Radiation fields # No RT Full mantle field only Full mantle field + infradiaphragmatic RT Other supradiaphragmatic field only Other supradiaphragmatic field + infradiaphragmatic RT Infradiaphragmatic RT only RT, field unknown 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 CT without procarbazine g/m 2 procarbazine > g/m 2 procarbazine >8.4 g/m 2 procarbazine CT, unknown if procarbazine Number of cycles with alkylating CT # * No CT CT, non-alkylating <4 cycles cycles cycles >10 cycles Unknown number of alkylating cycles CT, unknown if alkylating Splenectomy No Yes Unknown 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

7 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 ( ) ( ) 85.8 NR NR NR ( ) ( ) 17.9 Female ( ) ( ) ( ) ( ) ( ) 12.2 P- heterogeneity < Age at 1 st HL treatment years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) 19.9 P- trend < < <0.001 <0.001 <0.001 <0.001 < Follow-up duration 5-9 years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) 47.1 P- trend 0.82 < <0.001 <0.001 < < <0.001 Attained age; at HL <30 years ( ) ( ) ( ) 12.3 NR NR NR ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) 51.2 P- trend <0.001 <0.001 <0.001 < < <0.001 < Attained age; at HL <40 years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) 306 NR NR NR NR NR NR NR NR NR P- trend < < <

8 Table S3, continued Attained age; at HL <50 years ( ) ( ) ( ) ( ) 23.3 NR NR years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) ( ) ( ) ( ) years ( ) ( ) 361 NR NR NR NR NR 0.0 ( ) NR P- trend < < <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

9 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) na - - Female na Age P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity < 25 (ref) Period of treatment P -trend P -trend 0.63 P -trend P -trend (ref) Smoking #1 P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 Never smoker(ref) Former smoker Recent smoker Unknown

10 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 P -heterogeneity 0.20 Male (ref) Female 183 n.a Age P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 P -heterogeneity <0.001 < 25 (ref) Period of treatment P -trend 0.15 P -trend 0.22 P -trend P -trend < (ref) 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

11 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 ( ) RT ( ) No RT, no procarbazine ( ) No RT, procarbazine 4.2g/m ( ) No RT, procarbazine >4.2g/m ( ) RT, no procarbazine ( ) RT & procarbazine 4.2g/m ( ) RT & procarbazine >4.2g/m ( ) P- heterogeneity < Solid SMN above diaphragm* No RT above diaphragm ( ) RT above diaphragm ( ) No RT above diaphragm, no procarbazine ( ) No RT above diaphragm, procarbazine 4.2g/m ( ) No RT above diaphragm, procarbazine >4.2g/m ( ) RT above diaphragm, no procarbazine ( ) RT above diaphragm & procarbazine 4.2g/m ( ) RT above diaphragm & procarbazine >4.2g/m ( ) Lung & Bronchus: C34 No RT above diaphragm ( ) RT above diaphragm ( ) P- heterogeneity < No RT above diaphragm, no procarbazine ( ) No RT above diaphragm, procarbazine 4.2g/m ( ) No RT above diaphragm, procarbazine >4.2g/m ( ) RT above diaphragm, no procarbazine ( ) RT above diaphragm & procarbazine 4.2g/m ( ) RT above diaphragm & procarbazine >4.2g/m ( ) P- heterogeneity <

12 Table S5, continued Female breast: C50 No RT above diaphragm ( ) RT above diaphragm ( ) P- heterogeneity < No RT above diaphragm, no procarbazine No RT above diaphragm, procarbazine 4.2g/m ( ) No RT above diaphragm, procarbazine >4.2g/m ( ) RT above diaphragm, no procarbazine ( ) RT above diaphragm & procarbazine 4.2g/m ( ) RT above diaphragm & procarbazine >4.2g/m ( ) Thyroid: C73 No RT above diaphragm RT above diaphragm ( ) P- heterogeneity < No RT above diaphragm, no procarbazine No RT above diaphragm, procarbazine 4.2g/m No RT above diaphragm, procarbazine >4.2g/m RT above diaphragm, no procarbazine ( ) RT above diaphragm & procarbazine 4.2g/m ( ) RT above diaphragm & procarbazine >4.2g/m ( ) P- heterogeneity <0.001 Esophagus: C15 No RT above diaphragm ( ) RT above diaphragm ( ) P- heterogeneity No RT above diaphragm, no procarbazine ( ) No RT above diaphragm, procarbazine 4.2g/m No RT above diaphragm, procarbazine >4.2g/m ( ) RT above diaphragm, no procarbazine ( ) RT above diaphragm & procarbazine 4.2g/m ( ) RT above diaphragm & procarbazine >4.2g/m ( ) P- heterogeneity 0.42 <

13 Table S5, continued Solid SMN below diaphragm** No RT below diaphragm ( ) RT below diaphragm ( ) No RT below diaphragm, no procarbazine ( ) No RT below diaphragm, procarbazine 4.2g/m ( ) No RT below diaphragm, procarbazine >4.2g/m ( ) RT below diaphragm, no procarbazine ( ) RT below diaphragm & procarbazine 4.2g/m ( ) RT below diaphragm & procarbazine >4.2g/m ( ) Gastrointestinal: C16, C18-20, C25 No RT below diaphragm ( ) RT below diaphragm ( ) No RT below diaphragm, no procarbazine ( ) No RT below diaphragm, procarbazine 4.2g/m ( ) No RT below diaphragm, procarbazine >4.2g/m ( ) RT below diaphragm, no procarbazine ( ) RT below diaphragm & procarbazine 4.2g/m ( ) RT below diaphragm & procarbazine >4.2g/m ( ) NHL: C82-C88 No RT ( ) RT ( ) P- heterogeneity No RT, no procarbazine ( ) No RT, procarbazine 4.2g/m ( ) No RT, procarbazine >4.2g/m ( ) RT, no procarbazine ( ) RT & procarbazine 4.2g/m ( ) RT & procarbazine >4.2g/m ( ) P- heterogeneity

14 Table S5, continued Leukemia: C91-C96 No RT ( ) RT ( ) P- heterogeneity No RT, no procarbazine No RT, procarbazine 4.2g/m ( ) No RT, procarbazine >4.2g/m ( ) RT, no procarbazine ( ) RT & procarbazine 4.2g/m ( ) RT & procarbazine >4.2g/m ( ) 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

15 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 Other supradiaphragmatic with axilla Other supradiaphragmatic fields RT other & field unknown No RT No infradiaphragmatic RT Infradiaphragmatic RT with spleen Other infradiaphragmatic fields Number of alkylating cycles No CT CT, non-alkylating <4 cycles cycles cycles >10 cycles CT, unknown if alkylating agents Smoking <0.001 < Never smoker Former smoker Recent smoker Unknown

16 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 Full mantle field Other supradiaphragmatic with axilla Other supradiaphragmatic fields RT other & field unknown No RT < No infradiaphragmatic RT Infradiaphragmatic RT with spleen Other infradiaphragmatic fields Number of alkylating cycles <0.001 < No CT CT, non-alkylating <4 cycles cycles cycles >10 cycles CT, unknown if alkylating agents Splenectomy No Yes Unknown 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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abstract n engl j med 373;26 nejm.org December 24,

abstract n engl j med 373;26 nejm.org December 24, The new england journal of medicine established in 1812 December 24, 215 vol. 373 no. 26 Second Cancer Risk Up to 4 Years after Treatment for Hodgkin s Lymphoma Michael Schaapveld, Ph.D., Berthe M.P. Aleman,