5. Therapie früher Stadien – Hodgkin Lymphom

Referenz/
Studientyp

Untersuchte Studien

(verglichene) Interventionen

untersuchte Endpunkte

Hauptergebnisse

methodische Bemerkungen

Literaturbelege/
eingeschlossene Publikationen

(Blank, von Tresckow et al. 2017)

SR

Ia

RCTs searched in

• Cochrane Central Register of Controlled Trials from January 1977 to November 2010, for the update from December 2010 to December 2016
• MEDLINE (Ovid) from January 1977 to November 2010, for the update from December 2010 to December 2016
• Embase from January 1977 to June 2009
• Conference proceedings of the annual meetings of the following societies for abstracts (2000 to 2015, if not included in CENTRAL):
• American Society of Hematology (ASH)
• American Society of Clinical Oncology (ASCO)
• International Symposium on Hodgkin Lymphoma (IHSL) (update until 2013)
• Handsearching: We checked the reference lists of all identified trials, relevant review articles and current treatment guidelines for further literature.
• Personal contacts: We contacted experts in the field in order to retrieve information on unpublished trials

Inclusion criteria:

• RCTs comparing chemotherapy alone with combined modality treatment consisting of chemotherapy plus radiotherapy
• Treatment-naïve stage I and II HL
• newly diagnosed patients with early favourable and early unfavourable stages clinical stage (Voong, McSpadden et al.) I and CS II Hodgkin lymphoma (HL)

Exclusion criteria:

• RCTs comparing chemotherapy alone with chemotherapy plus radiotherapy in patients with all stages of HL if more than 20% of patients had advanced disease
• quasi- randomised trials
• trials including fewer than 10 patients per arm

Interventional group received chemotherapy and radiotherapy

Control group received conventional chemotherapy

Chemotherapy regimens:

ABVD in five trials

CVPP in one trial

EBVP in one trial

Radiation therapy regimens:

IFRT in three trials

EFRT in one trial

Mixed radiotherapy in one trial

Subtotal node radiotherapy in one trial

Involved-node radiotherapy in one trial

Authors defined two different cohorts for data analysis:

A: “Same number of chemotherapies in both arms”

B: “Different number of chemotherapies in both arms”

• Overall survival (mortality)
• Progression-free survival
• Treatment response
• Adverse events

7 trials reporting on 2564 patients included in review

Results: (A)

• OS (mortality)

HR: 0.31
95%CI: 0.19-0.50 (without trial and after 5 years)

• PFS

HR: 0.42
95%CI: 0.25-0.72

• Safety/AEs
• Infection related mortality:

RR: 0.33
95%CI: 0.01-8.06

• Second cancer related mortality:

RR: 0.53
95%CI: 0.07-4.29

• Cardiac related disease mortality:

RR: 2.94
95%CI: 0.31-27.55

• QoL: not reported
• Other relevant outcomes:
• Complete response rate:

RR: 1.08
95%CI: 0.93-1.25

Results: (B)

• OS (mortality)

HR: 2.12
95%CI: 1.03-4.37

• PFS

HR: 0.42
95%CI: 0.14-1.24

• Safety/AEs
• Infection related mortality:

RR: 6.90
95%CI: 0.36-132.34

• Second cancer related mortality:

RR: 2.22
95%CI: 0.70-7.03

• Cardiac related disease mortality:

RR: 0.99
95%CI: 0.14-6.90

• QoL: not reported

• Other:
• Complete response rate: not reported

Descriptive statistics: patient characteristics

• Gender: male > female
• Age: 15-75

Overall quality of included studies: moderate

Follow-Up: 5 years for OS and PFS

Randomisation: yes

ITT: Not sufficiently reported

Blinding: no

Funding: UKK Köln, Klinik I für Innere Medizin, BMBF

Heterogeneity:

• Random effects model
• I² = 52% (OS), I² = 69% (PFS), I² = 67% (CR)

Bloomfield 1982

(GALGB 7751)

Eghbali 2005 (EORTC‐GELA H9-F)

Raemakers 2014

 (H10F, H10U)

Meyer 2005 (HD6)

Aviles 1998 (Mexico B2H031)

Straus 2004 (MSKCC trial #90‐44)

Radford 2013 (RAPID trial)

SR

Gesamtüberleben

-

+¹

-

-

-

⊕⊕⊕⊝ moderate

Progressionsfreies Überbleben

-

+¹

-

-

-

⊕⊕⊕⊝ moderate

Behandlungsbedingte Mortalität

-

-

-

++²

-

⊕⊕⊝⊝ low 

Langzeitnebenwirkungen (Sekundärneoplasien)

-

-

-

++²

-

⊕⊕⊝⊝ low 

Lebensqualität

Not reported 

(Specht, Gray et al. 1998)

MA

randomized trials (N=3888)

• computer searches of medical literature data bases and the National Cancer Institute (Moore, Unger et al.) CLINPROT trial protocol data base
• lists prepared by the Union International Contre le Cancer (UICC)
• the United States NCI
• the United Kingdom Coordinating Committee on Cancer Research (UKCCCR)
• abstracts presented at meetings
• reference lists of published trials and review articles
• discussions with investigators

Inclusion criteria:

• early-stage HL
• trials from Western Europe and North America
• randomized in a manner that precluded prior knowledge of the next treatment assigned
• intention-to-treat analysis

Exclusion criteria:

• not reported

more vs less extensive RT (N=1974)

ChT + RT vs RT alone (N=1688)

• Risk of treatment failure
• OS

23 studies included in review

Results: more vs less extensive RT

• OS: at 10 yrs

• PFS: “There was a non-significant trend toward better progression-free survival with adaptive therapy”
• Safety/AEs: not reported
• QoL: not reported
• Other relevant outcomes:

Results: ChT + RT vs RT alone

• OS: at 10 yrs

ChT+RT=79.4%
RT alone=76.5%

• PFS: “There was a non-significant trend toward better progression-free survival with adaptive therapy”
• Safety/AEs: not reported
• QoL: not reported
• Other relevant outcomes

Risk of treatment failure (resistant or recurrent disease) at 10 yrs ( P < .00001):
ChT+RT=15.8%
RT alone=32.7%

Follow-Up: Follow-up periods are varying from trial to trial

Randomisation: yes

ITT: yes

Blinding: no

Funding: “Supported by the United Kingdom Imperial Cancer Research Fund; the Danish Medical Research Council; the European Community’s BIOMED program; and the United Kingdom Medical Research Council”

Heterogeneity:

marginally significant heterogeneity of effects (X², 11 df = 20.2; P = .04)

Trial groups included in this review: Baltimore Cancer Research

Program-Dutcher JP, Wiernik PH; British National Lymphoma Investigation Group-Vaughan Hudson G; Cancer and Leukemia Group

B-Anderson JR, Canellos GP, Propert KJ, Schiffer C; Children's Cancer Study Group-Hammond D; Eastern Cooperative Oncology

Group-Cassileth PA, McFadden E; European Organization for Research and Treatment of Cancer-Henry-Amar M, Meerwaldt JH, Noordijk EM;

German Hodgkin Study Group-Diehl V, Hasenclever D, L6ffier M; Groupe d'Etudes sur la Maladie de Hodgkin-Andrieu J-M, Teillet F; Groupe

Pierre et Marie Curie-Najman A, Eghbali H, Bonichon F; LYGRA Danish National Hodgkin Study-Nissen NI, Specht L; Manchester Lymphoma

Group-Crowther D, Deakin D, Swindell R; National CancerI nstitute of Canada-BergsagelD , Gospodarowicz M, Pater JL; United States National

Cancer Institute--Longo DL; Northern California Oncology Group-Hoppe RT; Oxford, Imperial Research Cancer Fund/Medical Research Council

Clinical Trial Service Unit (Secretariat)-Clarke MJ, Godwin J, Gray RG, Greaves E, Harwood C, Peto R, Wheatley K; Pediatric Oncology

Group-Sullivan MP, Fuller LM, Gehan E; Radiotherapy Hodgkin's Disease Group-Hutchison GB; Roswell Park Memorial Institute-Henderson

ES; St Jude Children's Research Hospital-Thompson EIl; Southwest Oncology Group--Coltman CA, Dahlberg S; Stanford-Rosenberg S, Hoppe RT; and Western Cancer Study Group--Chlebowski R.

SR

Gesamtüberleben

-

-

-

-

-

⊕⊕⊕⊕ high

Progressionsfreies Überleben

-

-

-

-

-

⊕⊕⊕⊕ high

Behandlungsbedingte Mortalität

Not reported 

Langzeitnebenwirkungen (Todesfälle durch Sekundärneoplasien)

-

-

-

++1

-

⊕⊕⊝⊝
low 

Lebensqualität

Not reported 

Referenz/ Studientyp

Untersuchte Population

Intervention

Kontrolle

untersuchte Endpunkte

Hauptergebnisse

methodische Bemerkungen

(Behringer, Goergen et al. 2015)

RCT

1b

n = 1502 patients

All patients were treated with 30GY IFRT after chemotherapy.

4-arm study

Inclusion Criteria:

• newly diagnosed, histologically proven, classic Hodgkin’s lymphoma in clinical stages I or II,
• nodular lymphocyte-pre dominant Hodgkin’s lymphoma in Ann Arbor stage IB, IIA, or IIB

Exclusion Criteria:

• large mediastinal mass (≥a third of the maximum thoracic diameter),
• extranodal lesions,
• raised erythrocyte sedimentation rate (≥50 mm/h without B symptoms, ≥30 mm/h with B symptoms),
• association of at least three nodal areas

Arm 1:
n = 566
2x ABVD

Baseline characteristics:

• Age: Median: 39
• Stage: (Ann Arbor) I A: 158, I B: 19, II A: 353, II B: 36
• Recurrence status: not reported

Arm 2:
n = 198
2x ABV

Baseline characteristics:

• Age: Median: 39 (recruited up to Feb, 2007)
• Stage: (Ann Arbor) I A: 63, I B: 5, II A: 118, II B: 12
• Recurrence status: not reported

Arm 3:
n = 571
2x AVD

Baseline characteristics:

• Age: Median: 40 (recruited up to Sept, 2009)
• Stage: (Ann Arbor) I A: 166, I B: 24, II A: 342, II B: 39
• Recurrence status: not reported

Arm 4:

n = 167
2x AV

Baseline characteristics:

• Age: Median: 37 (recruited up to Sept, 2005)
• Stage: (Ann Arbor) I A: 52, I B: 3, II A: 104, II B: 8
• Recurrence status: not reported

• OS
• PFS
• Treatment-related mortality
• Secondary neoplasms
• QoL

• OS: 5-year OS (HR: ABVD vs. others)

Arm 1: 97.6%
Arm 2: 94.1%
HR: 1.35 (95%CI: 0.61 to 2.96)
Arm 3: 97.6%
HR: 1.33 (95%CI: 0.67 to 2.63)
Arm 4: 98.1%
HR: 1.02 (95%CI: 0.41 to 2.51)

• PFS: 5-year PFS (HR: ABVD vs. others)

Arm 1: 93.5%
Arm 2: 82.1%
HR: 1.97 (95%CI: 1.15 to 3.38)
Arm 3: 89.6%
HR: 1.49 (95%CI: 0.98 to 2.26)
Arm 4: 78.9%
HR: 2.31 (95%CI: 1.34 to 3.96)

• AE:
• Leucopenia: 92 (Arm 1 ), 33 (Arm 2), 61 (Arm 3), 18 (Arm 4)
• Alopecia: 25 (Arm 1 ), 18 (Arm 2), 57 (Arm 3), 17 (Arm 4)
• Nausea/vomiting: 39 (Arm 1 ), 8 (Arm 2), 31 (Arm 3), 5 (Arm 4)
• Pain: 8 (Arm 1 ), 2 (Arm 2), 13 (Arm 3), 4 (Arm 4)
• Infection: 9 (Arm 1 ), 0 (Arm 2), 7 (Arm 3), 4 (Arm 4)
• Events in gastrointestinal tract: 11 (Arm 1 ), 1 (Arm 2), 5 (Arm 3), 0 (Arm 4)
• Events in respiratory tract: 3 (Arm 1 ), 0 (Arm 2), 0 (Arm 3), 1 (Arm 4)

• QoL: not reported
• Other:
• Treatment related mortality “[…] deaths due to toxic eff ects of fi rst-line treatment did not occur in this study, and the only death caused by respiratory tract disease in patients receiving bleomycin took place more than 8 years after treatment and was due to pneumonia”

• Secondary neoplasms

Not separately reported for different arms. 58 patients suffered from secondary malignancies.

• Study Duration: not reported
• Follow-up: 

Arm 1: 52 months (median)
Arm 2: 83 months
Arm 3: 55 months
Arm 4: 84 months

• ITT: Yes
• Randomisation: Yes
• Blinding: No, open label trial
• Funding: Study was funded by “Deutsche Krebshilfe and Swiss State Secretariat for Education and Research.”
• Other limitations: none 

(Canellos, Anderson et al. 1992)

RCT

1b

n = 400

39 patients excluded

Inclusion Criteria:

• > 16 years
• with histopathologically proven and untreated stage III A, III B, IV A or IV B HL or patients with recurrent HL after initial radiation (>3 three months between radiation and recurrence).

Exclusion Criteria:

• not reported

Arm 1:

n = 123

Six to eight cycles of MOPP mechlorethamine, vincristine, procarbazine, prednisone), depending on treatment response.

Patients on MOPP were switched to ABVD-arm in case of a) no evidence for complete response after six cycles or b) disease progression during therapy

Baseline characteristics:

• Age: median: 34
• Stage: III A₂: 15, III B: 19, IV A: 12, IV B: 36
• Recurrence status: not reported

Arm 2:

n = 115
Six to eight cycles of ABVD, depending on treatment response

 Baseline characteristics:

• Age: median: 35
• Stage: III A₂: 13, III B: 24, IV A: 12, IV B: 33
• Recurrence status: not reported

Arm 3:

n = 123
12 cycles of MOPP and ABVD given in alternation. (Patients without treatment response or progressive disease after four cycles were excluded)

Baseline characteristics:

• Age: median: 32
• Stage: III A₂: 15, III B: 24, IV A: 14, IV B: 32
• Recurrence status: not reported

• Treatment response
• Failure-free survival
• Overall survival
• Toxicity/AE

• OS: 5-year OS:

Arm1: 66%
Arm2: 73%
Arm3: 75%
P=0.28 (Arm 1 vs. Arm2+3)

• PFS: Disease progression

Arm1: 4%
Arm2: 2%
Arm3: 0%

• AE:
• Neutropenia: 47,21,1 (Arm 1); 18,3,0 (Arm 2); 53,28,0 (Arm 3); P < 0.001
• Thrombocytopenia: 36,15,1 (Arm 1); 2,3,0 (Arm 2); 28,13,0 (Arm 3); P < 0.001
• Anemia: 31,12,0 (Arm 1); 5,0,0 (Arm 2); 25,8,0 (Arm 3); P < 0.001
• Infection: 11,1,1 (Arm 1); 2,0,0 (Arm 2); 12,2,1 (Arm 3); P < 0.001
• Peripheral neuropathy: 8,0,0 (Arm 1); 1,0,0 (Arm 2); 2,0,0 (Arm 3); P < 0.001
• Alopecia: 5,0,0 (Arm 1); 24,0,0 (Arm 2); 14,0,0 (Arm 3); P < 0.001
• Nausea/vomiting: 28,0,0 (Arm 1); 33,0,0 (Arm 2); 39,0,0 (Arm 3); P = 0.09
• Pulmonary: 3,1,0 (Arm 1); 4,0,3 (Arm 2); 3,0,1 (Arm 3); P = 0.34

• QoL: not reported

• Other:
• Treatment response

CR
Arm1: 67%
Arm2: 82%
Arm3: 83%
P=0.006 (Arm 1 vs. Arm2+3)
Arm 1 vs. Arm 2:
Relative risk: 0.83
95%CI: 0.71-0.96)

PR
Arm1: 24%
Arm2: 13%
Arm3: 10%

• 5 year failure-free survival:

Arm1: 50%
Arm2: 61%
Arm3: 65%
P=0.02 (Arm 1 vs. Arm 2+3)
Arm1 vs. Arm2:
Relative risk: 0.69
95%CI: 0.47-1.02)
P=0.006

• Study Duration: not reported
• Follow-up: Median follow-up: 6 years
• ITT: No
• Randomisation: Yes
• Blinding: Not reported
• Funding: not reported

(Engert, Franklin et al. 2007)

RCT multicentre trial

1b

n = 650

Inclusion Criteria:

• Newly diagnosed Histology-proven HL
• IA-IIB without risk factors
• 16 – 75 years
• Karnofsky performance status > 70%
• previously untreated
• free of concurrent disease

Exclusion Criteria:

• impaired heart, lung, liver, or kidney function, previous malignant disease, or HIV-positive status
• chronic obstructive lung disease
• pregnant or lactating
• HL as part of a composite lymphoma

Arm 1:

n = 311
EFIF

Baseline characteristics:

• Age: median: 38
• Stage: I A: 41, I B: 3, II A: 54, II B: 2
• Recurrence status: not reported

Arm 2:

n = 316
2xABVD + EFIF

Baseline characteristics:

• Age: median: 34
• Stage: I A: 43, I B: 3, II A: 50, II B: 4
• Recurrence status: not reported

• OS
• CRR
• FFTF
• Toxicity Grade 3/4
• TRD
• PFS
• CR

• OS: EFIF: 92% ; P=0.43, ABVD:94% ; P=0.43

• PFS: not reported

• AE: Arm 1 RT: n = 271, Arm 2 RT: n =261; Grade 3[%]+4[%]
• Leukopenia: 2,6 (Arm 1); 0,8 (Arm 2)
• Nausea: 3,3 (Arm 1); 5,4 (Arm 2)
• Infection: - (Arm 1); 0,4 (Arm 2)
• Skin: - (Arm 1); 2,7 (Arm 2)
• Pharynx: 2,6+0,4 (Arm 1); 1,5+0,4 (Arm 2)
• Larynx: 0,4 (Arm 1); 0,4+0,4 (Arm 2)
• Esophagus: 2,2+0,4 (Arm 1); 0,8+0,4 (Arm 2)

• QoL: not reported

• Other:
• CRR :

EFIF:95% ; ABVD:94%
P: nr
FFTF:
EFIF: 67% (95%CI, 61%-73%)
ABVD: 88% (95%CI; 84%-92%; P<0.0001)

• ABVD-toxicity:

• RT-toxicity:
• leukopenia 2.6
• TRD:
• EFIF: 4.2%
• ABVD: 2.5%

• Study Duration: not reported
• Follow-up: 87 months
• (n=23 patients were excluded from analysis; n=8 in treatment arm and n=22 dropped out)
• ITT: No, For ABVD-toxicity 10% were not included in analysis, For RT-toxicity 13% in EFIF arm and 17% in ABVD-EFIF were not included in analysis
• Randomisation: Yes
• Blinding: No, Blinding not possible because no placebo was used in control group
• Funding: Deutsche Krebshilfe, Swiss Group for Clinical Cancer Research
• Other limitations: none

(Engert, Plutschow et al. 2010b)

RCT (HD10)

NCT00265018

n = 1190

Inclusion Criteria:

• Newly diagnosed
• untreated
• 16 to 75 years
• Favourable prognosis
• Confirmed histologic examination
• No clinical risk factors

Exclusion Criteria:

Not reported

Arm 3:

n = 295
2xABVD + 30Gy

Baseline characteristics:

• Age: mean: 38,3
• Stage: (Ann Arbor) I A: 99, I B: 7, II A: 175, II B: 14
• Recurrence status: not reported

Arm 4:

n = 299
2xABVD + 20Gy

Baseline characteristics:

• Age: mean: 38,7
• Stage: (Ann Arbor) I A: 76, I B: 6, II A: 197, II B: 20

Recurrence status: not reported

Arm 1:
n = 298
4xABVD +30Gy

Baseline characteristics:

• Age: mean: 39,5
• Stage: (Ann Arbor) I A: 94, I B: 5, II A: 182, II B: 17
• Recurrence status: not reported

Arm 2:
n = 298
4xABVD + 20Gy

Baseline characteristics:

• Age: mean: 38,6
• Stage: (Ann Arbor) I A: 92, I B: 6, II A: 184, II B: 15
• Recurrence status: not reported

• FFTF
• OS
• PFS
• CR
• Toxicity

• OS: Arm 1/2: 97.1%; P=0.61, Arm 3/4: 96.6%; P=0.61, Arm 1/3: 97.7%; P=0.61, Arm 2/4: 97.5%; P=0.61

• PFS: (95% CI)
  5 years [%]:
  93.9 (Arm 1), 93.2 (Arm 2), 90.8 (Arm 3), 91.6 (Arm 4)
  8 years [%]:
  88.4 (Arm 1), 90.0 (Arm 2), 85.4 (Arm 3), 86.5 (Arm 4)
• AE:
• (at least one instance of severe) Toxicity (grade III/IV): 51.7% (Arm 1+2) vs. 33.2% (Arm 3+4) (P<0.001); 8.7% (Arm 1+3) vs. 2.9% (Arm 2+4) (P<0.001).
• hair loss: 28.1% (Arm 1+2) vs. 15.2% (Arm 3+4)
• hematologic toxic effects: 24.0% (Arm 1+2) vs. 15.0%(Arm 3+4)
• Infections: 5.1% (Arm 1+2) vs. 1.7% (Arm 3+4)
• Treatment-related deaths: 6 patients (Arm 1+2) (two died from pulmonary fibrosis, two from sepsis, one from pneumonia, and one from an unspecified cause) vs. 1 patient (Arm 3+4) (from pulmonary fibrosis)
• Secondary neoplasia: Arm 1/2: 4.5%, Arm 3/4: 4.7%

• QoL: “better quality of life associated with shorter and less intense treatment”

• Other:
• FFTF: Arm 1/2: 93%; P=0.39, Arm 3/4: 91.1%; P=0.39, Arm 1/3: 93.4%; P=0.39, Arm 2/4: 97.5% ; P=0.39
• TRD: Arm 1/2:1.5%, Arm 3/4: 2.3%
• CR: Arm 1/2: 96.5%; P=nr, Arm 3/4: 96,8%; P=nr, Arm 1/3: 99%; P=nr, Arm 2/4: 97.4%; P=nr

• Study Duration: not reported
• Follow-up: Yes, 80 month (Arm 1 + 3), 77 months (Arm 2 + 4)
• ITT: Yes, Intention-to-treat principle was used on the basis of the treatment actually received
• Randomisation: Yes, “randomly assigned centrally in a 1:1:1:1 ratio”, Reported that randomisation was performed centrally, Insufficient information available on allocation concealment to permit judgement
• Blinding: No, Blinding not possible because no placebo was used in control group
• Funding: Deutsche Krebshilfe, Swiss Federal Government
• Other limitations: none

(Sasse, Brockelmann et al. 2017)

Siehe Engert 2007, hier mit Studienupdate HD7 extrahiert

• PFS (15-year follow up, 95% CI)
• EF-RT: 52.2% (44.9%-59.5%)
• CMT: 72.8% (65.6%-80.0%)
• HR=0.45 (0.3-0.6)
• Median observation time, 120 months

• OS (15-year follow-up, 95% CI)
• EF-RT: 77.1% (71.2%-83.0%)
• CMT: 79.7% (73.9%-85.6)
• HR=0.8 (0.6-1.2)
• Median observation time, 136 months

• Long-term follow-up:
• Second neoplasia (15-year cumulative incidence, %, 95% CI)):
• EF-RT: 16 (11-22)
• CMT: 14 (9-19)

• Standardized incidence rate (95% CI):
• EF-RT: 2.7 (1.9-3.6)
• CMT: 3.0 (2.2-4.0)

(Sasse, Brockelmann et al. 2017)– Update zu HD10 (Engert, Plutschow et al. 2010b))

Siehe Engert 2010, für diese Empfehlung: nur HD10 aus Sasse 2017 extrahiert

• 10-year PFS
• 10-year OS

• 10-year PFS
• Non-inferiority of least intensive (2xABVD + 20Gy RT) compared to most intensive (4xABVD + 30 Gy RT) was confirmed, 87% in both groups,

• 4ABVD+30Gy: 87.4% (82.9-91.9%)
• 2ABVD+20Gy: 87.2% (82.9-91.5%)
• HR = 1 (95% CI, 0.6-1.5 within margin of 2.2)
• Median observation time, 98 months 

• 10-year OS
• 4ABVD+30Gy: 93.6% (90.5-96.7%)
• 2ABVD+20Gy: 94.1% (91.1%-97.1%)
• HR = 0.9 (95% CI, 0.5 to 1.6)
• Median observation time, 113 months

• Long-term follow-up:
• Second neoplasia (10-year cumulative incidence, %, 95% CI)):
• 4ABVD+30Gy: 8 (5-12)
• 4ABVD+20Gy: 6 (3-10)
• 2ABVD+30Gy: 8 (4-11)
• 2ABVD+20Gy: 9 (5-11)

• Standardised incidence ratio (95% CI):
• 4ABVD+30Gy: 2.1 (1.4-3.1)
• 4ABVD+20Gy: 1.5 (0.9-2.3)
• 2ABVD+30Gy: 1.6 (1.0-2.5)
• 2ABVD+20Gy: 2.1 (1.4-3.2)

RCTs

Gesamtüberleben

-

-

-

-

-

⊕⊕⊕⊕ high

Progressionssfreies Überleben

-

-

-

-

-

⊕⊕⊕⊕ high

Behandlungsbedingte Mortalität

-

-

-

++1

-

⊕⊕⊝⊝ low 

Langzeitnebenwirkungen (Todesfälle durch Sekundärneoplasien)

-

-

-

++1

-

⊕⊕⊝⊝ low 

Lebensqualität

Not reported 

RCTs

Gesamtüberleben

-

-

-

-

-

⊕⊕⊕⊕ high

Progressionsfreies Überleben

-

-

-

-

-

⊕⊕⊕⊕ high

Behandlungsbedingte Mortalität

-

-

-

++1

-

⊕⊕⊝⊝ low 

Langzeitnebenwirkungen (Todesfälle durch Sekundärneoplasien)

-

-

-

++1

-

⊕⊕⊝⊝ low 

Lebensqualität

Not reported 

SRs

Gesamtüberleben

-

+¹

-

-

-

⊕⊕⊕⊝ moderate

Progressionsfreies Überleben

-

+¹

-

-

-

⊕⊕⊕⊝ moderate

Behandlungsbedingte Mortalität

-

-

-

++²

-

⊕⊕⊝⊝ low 

Langzeitnebenwirkungen (Sekundärneoplasien)

-

-

-

++²

-

⊕⊕⊝⊝ low 

Lebensqualität

Not reported 

SRs

Gesamtüberleben

-

+¹

-

-

-

⊕⊕⊕⊕ high

Progressionsfreies Überleben

-

+¹

-

-

-

⊕⊕⊕⊕ high

Behandlungsbedingte Mortalität

-

-

-

++²

-

Not reported 

Langzeitnebenwirkungen (Sekundärneoplasien)

-

-

-

++²

-

⊕⊕⊝⊝ low 

Lebensqualität

Not reported 

RCTs

Gesamtüberleben

-

-

-

-

-

⊕⊕⊕⊕ high

Progressionsfreiees Überleben

-

-

-

-

-

⊕⊕⊕⊕ high

Behandlungsbedingte Mortalität

-

-

-

++1

-

⊕⊕⊝⊝ low 

Langzeitnebenwirkungen (Todesfälle durch Sekundärneoplasien)

-

-

-

++1

-

⊕⊕⊝⊝ low 

Lebensqualität

Not reported 

(Antoni, Natarajan-Ame et al. 2013)

Prospective case series

n = 13

Patients received 30 Gy radiotherapy in 15 fractions and a boost of 6 Gy in three fractions.

Inclusion Criteria:

• Female
• Newly diagnosed supradia-phragmatic stage IIA or IIB HL
• Treated by ABVD ± BEACOPP

Exclusion Criteria:

• Not reported

Baseline characteristics:

• Age: median: 29.7
• Stage: II A: 12, II B: 1
• Recurrence status: not reported

intensity-modulated radiotherapy by helical tomography (IMRT-HT)

3D-conformal radiotherapy (3D-CRT)

• Planned target volume (PTV)
• Target dosimetry
• Organ doses

• OS: (2- and 3-year): 100%

• PFS: (2-year): 91.6%

• AE: not reported 

• QoL: not reported

• Other:
• PTV:
  Median PTV was 970cm3 (range: 512-2666cm3)
  Mean dose: 3D-CRT 100.6%, IMRT-HT: 100%, No statistical significant difference, Percent of PTV within 95% isodose, 3D-CRT: 93.7%, IMRT-HT: 95.8%, No statistical significant difference,

• Target dosimetry:
  “The conformity index was better for IMRT than for 3DCRT, at 1.2 and 2.4, respectively (p=0.001).”, “The median cover index was 0.8 (range: 0.4-08) for IMRT and 0.6, (range 07–0.9) for 3D-CRT (p=0.001).”

• Organ doses:
  “The mean average dose was significantly higher for 3DCRT than for IMRT in case of esophagus (24.6 vs. 21.5 Gy, p= 0.002), lung (12.4 vs. 9.7, p=0.003) and heart (13.9 Gy vs. 11.5 Gy, p=0.01), “For both breast volumes, the median maximal dose was significantly lower for IMRT than for 3D-CRT, at 35.3 Gy and 38.6 Gy, respectively (p = 0.001).”, “The mean average, maximum and minimal doses for [For thyroid gland] were not significantly different for 3D-CRT compared with IMRT, at 30.1 and 29.4 Gy, 37.2 and 37.1 Gy and 13.9 and 15.1 Gy, respectively”

• Study Duration: not reported
• Follow-up: Median follow-up was 23 months
• ITT: No
• Randomisation: No
• Blinding: No
• Funding: not reported
• Other limitations: treatment planning study, simulation?

(Baues, Marnitz et al. 2018)

n = 21

Recruitment: 2014 - 2016

Inclusion criteria:

• all patients with Hodgkin lymphoma and mediastinal involvement were consecutively included

Exclusion criteria:

• Not reported 

Baseline characteristics:

• Age (mean): 34 years
• Stage: stages I-IV
• 16 women, 5 men

intensity

modulated radiotherapy (IMRT), in the form of volumetric modulated arc therapy (VMAT), 30 Gy to the PTV

(deep inspiration breath hold)

• Clinical target volume (CTV)
• planning target volume (PTV)
• Dose to spinal cord
• dose to left breast
• Dose to right breast
• Dose to lungs
• Dose to heart
• Dose to heart wall
• Dose to healthy tissue

• CTV (Mean, sd, in Gy)

IMPT: 30.1 (0.2)

RA (VMAT): 30.6 (0.2)

n.s.

• PTV planning tumor volume (Mean, sd, in Gy)

IMPT: 30.0

RA (VMAT): 30.0 

• Dose to spinal cord (D1%, sd, in gy)

IMPT: 15.9 (5.6)

RA (VMAT): 20.3 (5.2)

P<0.01, Difference: 22%

• Dose to left breast (Mean, sd, in Gy)

IMPT: 0.6 (0.9)

RA (VMAT): 3.5 (2.8)

P<0.01, Difference: 83%

• Dose to right breast (Mean, sd, in Gy)

IMPT: 0.7 (1.7)

RA (VMAT): 3.7 (3.8)

P<0.01, Difference: 81%

• Dose to lungs (Mean, sd, in Gy)

IMPT: 4.3 (1.8)

RA (VMAT): 7.9 (3.0)

P<0.01, Difference: 46%

• Dose to heart (Mean, sd, in Gy)

IMPT: 4.1 (3.9)

RA (VMAT): 6.6 (4.6)

P<0.01, Difference: 38%

• Dose to heart wall (Mean, sd, in Gy)

IMPT: 2.9 (4.0)

RA (VMAT): 4.9 (4.6)

P<0.01, Difference: 40%

• Dose to healthy tissues (Mean, sd, in Gy)

IMPT: 2.3 (1.5)

RA (VMAT): 4.5 (2.1)

• P<0.01, Difference:49 %

• Study Duration: 2 years
• Follow-up: not applicable
• ITT: no
• Randomisation: no, each treatment plan for every person
• Blinding: no
• Funding: not reported
• Other limitations: non-RCT treatment planning study

(Cella, Conson et al. 2013)

Case Report

n = 1

Inclusion Criteria:

• One case of a female HL patient with solely supradiaphragmatic tumor spread 

Exclusion Criteria:

• not reported

Baseline characteristics:

• Age: not reported
• Stage: not reported
• Recurrence status: not reported

n = 1

Simulation five treatment radiation techniques (anterior-posterior parallel opposed technique (AP-PA), forward intensity modulated technique (FIMRT), inverse intensity modulated technique (IMRT), Tomotherapy technique (Arakelyan, Jais et al.) and proton technique (PRO))

• Planned targeted volume (PTV)
• Target dose
• Organ dose

• “IMRT, TOMO and PRO plans generally reduced the OARs’ dose and accordingly the related radio-induced toxicities”

• “IMRT and TOMO plans an increased risk of  development of breast, and lung SMN compared with AP-PA and FIMRT techniques was estimated”

• “Only PRO plans seemed to reduce the risk of predicted SMN compared with AP-PA technique.”

• Study Duration: not reported
• Follow-up: not reported
• ITT: -
• Randomisation: -
• Blinding: -
• Funding: “This work was partially supported by grants from Italian Ministry for Education, University and Research (MIUR) in the framework of FIRB (RBNE08YFN3 “MERIT”).”
• Other limitations: Simulation study

(Cella, Liuzzi et al. 2010)

Retrospective case series

4

n = 10

Patients received a total dose of 30 Gy fractioned to 1.5 Gy per session

Each treatment plan was calculated for each patient

Inclusion Criteria:

• Patients with supradiaphragmatic stage II HL undergoing postchemotherapy radation with a planning target volume >900m3.

Exclusion Criteria:

• Not reported 

Baseline characteristics:

• Age: 18-42
• Stage: II A: 4, II B: 2, III AS: 1, III BS: 1, IV AS: 1, IV B: 1
• Recurrence status: not reported

forward planned intensity modulated

Technique (FPIMRT) or

conventional parallel-opposed field plan (AP-PA).

• Planned target volume
• Target dose
• Organ doses

• PTV:

Mean PTV was 1,652cm3 (95%CI: 1,191 to 2,112)
Mean dose

• AP-PA: 105%
• FPIMRT: 101%
• P<0.001
• Percent of PTV within 95% isodose
• AP-PA: 95.9%
• FPIMRT: 96.8%
• P=0.05

• Target dose: Mean and maximal dose were significantly lower for FPIMRT technique, but minimal dose did not differ significantly between both techniques.

• Organ doses: Organ doses of both plans were comparable for heart, lung and breast. For spinal cord, the FPIMRT technique significantly reduced the maximum dose and for the thyroid glaned the FPIMRT approach significantly reduced the minimum, maximum and average dose.
• Lung (mean values, 95% CI of predicted NTCPs):
• APPA: 7.3 (3.6-11.6)
• FPIMRT: 6.2 (2.8-9.6)
• Heart (mean values, 95% CI of predicted NTCPs):
• APPA: 0.3 (0-0.7)
• FPIMRT: 0.3 (0-0.8)
• Spinal cord:
• APPA: 2.1 (1.6-2.6)
• FPIMRT: 1.6 (1.3-1.9)
• Thyroid:
• APPA: 1.6 (8.1-15.2)
• FPIMRT: 7.6 (5.4-9.8)

• Study Duration: not reported
• Follow-up: not reported
• ITT: not reported
• Randomisation: not reported
• Blinding: not reported
• Funding: not reported
• Other limitations: treatment planning study, simulations

(Edvardsson, Kugele et al. 2019)

n = 18

Recruitment: 2014-2017

Before radiation therapy (RT), 2 planning CTs were acquired

- one with deep inspiration breath hold (DIBH)

  - one with free breathing (FB)

Inclusion criteria:

• Mediastinal HL

Exclusion criteria:

• Not reported

Baseline characteristics:

• Age (median): 34 years (range 15-71 years)
• Stage: IIA: 9, IIB: 3, III: 4, IV: 1
• 8 male, 10 female

intensity modulated

Proton Therapy (IMPT)

3-dimensional conformal radiation therapy (3D-CRT)

 volumetric modulated arc therapy (VMAT)

• Clinical target volume (V95%, in %)

FB 3D-CRT: 97.7 (90.9 100)

DIBH 3D-CRT: 97.3 (91.1-99.9)

FB VMAT: 100 (100-100)

DIBH VMAT: (100 (100-100)

FB IMPT: 99.9 (97.8-100)

DIBH IMPT: 99.6 (98.4-100)

P<0.001

• Planning target volume (V95%, in %)
• Dose to heart (median mean dose, range, in Gy(RBE))

FB 3D-CRT: 8.8 (0.5-22.9)

DIBH 3D-CRT: 7.7 (0.5-27.3)

FB VMAT: 6.7 (0.4-18.3)

DIBH VMAT: 5.3 (0.5-20.6)

FB IMPT: 6.1 (0.0-17.6)

DIBH IMPT: 3.8 (0.1-20.9)

P<0.001

• Dose to left anterior descending coronary artery (median mean dose, range, in Gy(RBE))

FB 3D-CRT: 15.2 (0.7-30.4)

DIBH 3D-CRT: 13.9 (0.7-26.9)

FB VMAT: 13.0 (0.7-30.1)

DIBH VMAT: 5.6 (0.7-22.7)

FB IMPT: 12.9 (0.1-29.8)

DIBH IMPT: 8.1 (0.1-23.1)

P<0.001

• Dose to lungs (median mean dose, range, in Gy(RBE))

FB 3D-CRT: 8.8 (4.2-18.8)

DIBH 3D-CRT: 7.2 (3.8-15.8)

FB VMAT: 6.7 (4.0-14.2)

DIBH VMAT: 6.2 (3.6-14.1)

FB IMPT: 5.2 (1.9-13.8)

DIBH IMPT: 4.5 (1.8-12.2)

P<0.001

• Dose to left breast ((median mean dose, range, in Gy(RBE))

FB 3D-CRT: 2.1 (0.3-10.0)

DIBH 3D-CRT: 1.6 (0.5-5.6)

FB VMAT: 2.2 (0.5-7.0)

DIBH VMAT: 2.3 (0.5-5.3)

FB IMPT: 0.5 (0.0-2.6)

DIBH IMPT: 0.7 (0.0-2.1)

P<0.001

• Dose to right breast (median mean dose, range, in Gy(RBE))

FB 3D-CRT: 1.9 (0.4-8.5)

DIBH 3D-CRT: 2.3 (0.5-9.9)

FB VMAT: 1.4 (0.4-5.3)

DIBH VMAT: 2.1 (0.4-5.1)

FB IMPT: 0.3 (0.0-3.0)

• DIBH IMPT: 0.5 (0.0-4.2)

• Study Duration: not reported
• Follow-up: not applicable
• ITT: no
• Randomisation: no, each treatment plan for every person
• Blinding: no
• Funding: not reported
• Other limitations: non-RCT treatment planning study (simulation)

(Filippi, Ragona et al. 2015)

Prospective case series

4

n = 38

Inclusion Criteria:

• Early stage HL (I-IIA, only mediastinal or neck involvement)
• Treated with ABVD followed by 30 Gy radiotherapy (Involved Node RT or Involved Side RT)

Exclusion Criteria:

• Axillary involvement

Baseline characteristics:

• Age: median 30, range 15-43 years
• Stage: I: 8, II: 30
• 13 male, 25 female

n = 13
3D-CRT (3-dimensional conformal radiation therapy)

n = 25
VMAT (volumetric modulated arc therapy)

• Planned target volume (PTV)
• Organ dose

AER (absolute excess risk, sd):

• Cardiac diseases

3D-CRT: 0.74 (1.5)

VMAT: 0.37 (0.45)

P = 0.38

• Aortic diseases

3D-CRT: 2.15 (2.27)

VMAT: 0.26 (0.63)

P < 0.0001

• Pulmonic diseases

3D-CRT: 3.13 (3.24)

VMAT: 1.36 (1.88)

P<0.0001 

• Mitral valve

3D-CRT: 0.29 (1.10)

VMAT: 0.003 (0.007)

P =0.12

• Tricuspid valve

3D-CRT: 0.73 (2.11)

VMAT: 0.07 (0.36)

P = 0.045

• All valves

3D-CRT: 1.57 (2.55)

VMAT: 0.42 (1.14)

P < .0001

• Other:
• PTV

Percent of PTV within 95% isodose
3D-CRT: 94.99 (1.02)
VMAT: 93.00 (0.74)

• Organ equivalent doses (mean)
• Lung

• VMAT: 2.28  (0.73)

P=0.025

• Thyroid

3D-CRT: 3.29 (1.77)
VMAT: 3.34 (1.75)
P=0.35

• Breast (female)

3D-CRT: 0.22 (0.15)
VMAT: 0.22 (0.16)
P=0.72

• Study Duration: not reported
• Follow-up: Not reported
• ITT: Not reported
• Randomisation: Not reported
• Blinding: Not reported
• Funding: Not reported
• Other limitations: none

(Girinsky, Pichenot et al. 2006)
Not controlled

n = 12

Recruitment: 2003-2004

Prescription dose was 40Gy in 2-Gy fractions, treatment with IMRT

Inclusion Criteria:

• Mediastinal HL
• Previously treated with ABVD

Exclusion Criteria:

• Not reported

Baseline characteristics:

• Age: median: 30
• Stage: not reported
• Recurrence status: not reported

intensity modulated radiotherapy (IMRT)

five different treatment plans have been used for IMRT

3 dimensional conformal radiotherapy (3D-CRT)

Conventional therapy (AP fields)

• Planned target volume (PTV)
• Organ dose

• PTV:

PTV<95%
AP: 6.9
3D-CRT: 6.4
IMRT: 2.9
Use of IMRT reduced PTV<95% significantly compared to AP (p=0.006) or in comparison with 3d-CRT (p=0.031)

• Organ dose (median)
• Heart
• AP: 7.8 Gy

3D-CRT: 9.1 Gy

IMRT: 7.7 Gy, Use of IMRT reduced organ dose significantly compared to AP or in comparison with 3d-CRT

• Lung

AP: 4.3 Gy

3D-CRT: 10.8 Gy

IMRT: 10 Gy

• Breast

AP: 0.3 Gy

3D-CRT: 0.7 Gy

IMRT: 1.2 Gy, Use of IMRT reduced organ dose significantly compared to AP or in comparison with 3d-CRT

• Esophagus (mean)

AP: 33.3 Gy

3D-CRT: 31.6 Gy

IMRT: 28.7 Gy, Use of IMRT reduced organ dose significantly compared to AP or in comparison with 3d-CRT

• Spinal cord (mean)

AP: 27 Gy

3D-CRT: 23.5 Gy
IMRT: 15.5 Gy, Use of IMRT reduced organ dose significantly compared to AP or in comparison with 3d-CRT

• Study Duration: not reported
• Follow-up: not applicable
• ITT: Not reported
• Randomisation: Not reported
• Blinding: Not reported
• Funding: Not reported
• Other limitations: treatment planning study - simulation

(Koeck, Abo-Madyan et al. 2012)

Prospective case series

5

n = 20

Prescription dose was 30 Gy as median PTV dose.

Inclusion Criteria:

• Mediastinal HL
• Treated with chemotherapy followed by radiation

Exclusion Criteria:

• Not reported

Baseline characteristics:

• Age: not reported
• Stage: not reported
• Recurrence status: not reported
• 10 male, 10 female

intensity modulated radiotherapy (IMRT) calculation based on a) Pencil beam oder b) collapsed cone

3 dimensional conformal radiotherapy (3D-CRT) calculation based on a) Pencil beam or b) Collapsed cone algorithm

• Planned target volume
• Organ dose

• IMRT
• PTV (mean)
• Pencil beam: 29.94 Gy

Monte Carlo: 29.75 Gy
P<0.001

• Organ dose (mean)
• Heart
• Pencil beam: 13.2 Gy
• Monte Carlo: 13.76 Gy
• P=0.07
• Organ dose (mean)
• Lung
• Pencil beam: 12.63 Gy
• Monte Carlo: 12.77 Gy
• P=0.78
• Spinal cord
• Pencil beam: 19.41 Gy
• Monte Carlo: 19.16 Gy
• P=0.10
• female right breast
• Pencil beam: 4.27 Gy
• Monte Carlo: 4.30 Gy
• P=0.84
• female left breast
• Pencil beam: 4.37 Gy
• Collapsed cone: 4.79 Gy
• P=0.064

• 3D-CRT
• PTV

The average PTV was 1,705cm3 (range: 979 to 3144).
3D-CRT:
PTV (mean)
Pencil beam: 29.89 Gy
Collapsed cone: 29.68 Gy
P=0.0012

• Organ dose (mean)
• Heart
• Pencil beam: 18.22 Gy

Collapsed cone:
17.94 Gy
P=0.70

• Lung
• Pencil beam: 10.30 Gy
• Collapsed cone: 10.62 Gy
• P<0.001
• Spinal cord
• Pencil beam: 23.66 Gy
• Collapsed cone:23.93 Gy
• P<0.001
• Female left breast
• Pencil beam: 2.96 Gy
• Collapsed cone: 3.17 Gy P=0.67
• Female right breast
• Pencil beam: 1.80 Gy
• Collapsed cone: 1.84 Gy
• P=0.015

• Study Duration: not reported
• Follow-up: Not reported
• ITT: Not reported
• Randomisation: Not reported
• Blinding: Not reported
• Funding: Not reported
• Other limitations: treatment planning study, simulation

(Maraldo, Brodin et al. 2013a)

Individual case-Control Study

3b

n = 27

Recruitment: 2006-2010

Inclusion Criteria:

• Stage I-II mediastinal HL
• supradiaphragmatic disease
• classical histology
• age ≥15 years
• planning computed tomography (Falorio, Biasoli et al.) scanning including both the neck and the mediastinum

Exclusion Criteria:

• lymphocyte predominance-histology
• chemotherapy given at other institutions
• unplanned modifications in radiotherapy 

Baseline characteristics:

• Age: median: 27
• Stage: II A: 13, II EA: 1, II B: 13
• Recurrence status: not reported

Simulation of MF (36 Gy),

INRT-VMAT and INRT-PT (30 Gy)

ABVD regimen followed by INRT delivered as 3D-CRT, pre-chemotherapy 18-flourodeoxy-glucose positron emission tomography/CT scan, post-chemotherapy CT scan

• Organ doses

• Risk estimations
• Cardiac mortality: 1.0 (3D CRT), 1.1 (VMAT), 0.9 (De Bruin, Huisbrink et al.), 2.9 (MF)
• Cardiac morbidity: 1.3 (3D CRT), 1.3 (VMAT), 1.1 (De Bruin, Huisbrink et al.), 8.6 (MF)
• Myocardial infarction: 5.5 (3D CRT), 5.9 (VMAT), 4.7 (De Bruin, Huisbrink et al.), 19.8 (MF)
• Valvular disease: 0 (3D CRT), 0 (VMAT), 0 (De Bruin, Huisbrink et al.), 0.4 (MF)
• Radiation-induced lung cancer: 4.4 (3D CRT), 6.0 (VMAT), 3.3 (De Bruin, Huisbrink et al.), 10.5 (MF)
• Radiation-induced breast cancer: 3.7 (3D CRT), 8.0 (VMAT), 1.4 (De Bruin, Huisbrink et al.), 23.0 (MF)
• Life years lost: 0.9 (3D CRT), 1.1 (VMAT), 0.7 (De Bruin, Huisbrink et al.), 2.1 (MF) 

• Organ doses
• Heart (median mean dose)
• 3D-CRT: 9.9 Gy
• VMAT: 10.1 Gy
• PT: 8.2 Gy
• MF: 27.2 Gy
• 3D-CRT vs. VMAT: P=0.335
• 3D-CRT vs. PT: P<0.0001
• VMAT vs. PT: P<0.0001
• Lung (median mean dose)
• 3D-CRT: 8.6 Gy
• VMAT: 11.4 Gy
• PT: 7.3 Gy
• MF: 20 Gy
• 3D-CRT vs. VMAT: P<0.0001
• 3D-CRT vs. PT: P<0.0001
• VMAT vs. PT: P<0.0001
• Breast (females, median mean dose)
• 3D-CRT: 3.0 Gy
• VMAT: 7.5 Gy
• PT: 1.1 Gy
• MF: 20.1 Gy
• 3D-CRT vs. VMAT: P=0.002
• 3D-CRT vs. PT: P=0.003

• Study Duration: not reported
• Follow-up: Not reported
• ITT: Not reported
• Randomisation: Not reported
• Blinding: Not reported
• Funding:  The study “was supported by the Rigshospitalet Scientific Committee.”
• Other limitations: treatment planning study, simulation

(Maraldo, Brodin et al. 2014),

Same patients as above (Maraldo, Brodin et al. 2013a), but different organs calculated

n = 37

Recruitment: 2006-2010

Inclusion criteria:

• Patients ≥ 15 years old
• Treated with INRT
• Clinical stage I-II
• cervical involvement

Exclusion criteria:

• Not reported

Baseline characteristics:

• Age (median): 33 years (range 15-76 years)
• Stage: I-IIB
• 18 male, 19 female
• Pretreatment mainly ABVD only (91.9%)

Simulations for:

VMAT–INRT (30.6 Gy)

PT–INRT (30.6 Gy)

MF plan (36 Gy)

3DCRT–INRT (30.6 Gy). A

• Dose to thyroid gland (median mean dose, in Gy)

3D-CRT: 15.3 Gy

VMAT: 19.3 Gy

PT: 15.4 Gy

MF: 37.3 Gy

P < 0.0001

Vergleich 3DCRT vs.PT (p = 0.14)

• Dose to neck muscles (median mean dose, in Gy)

3D-CRT: 10.9 Gy

VMAT: 12.0 Gy

PT: 7.9 Gy

MF: 34.5 Gy

P < 0.0001

Vergleich 3DCRT vs.PT (p = 0.01, dose lower for PT)

Vergleich PT vs VMAT (p < 0.0001, dose lower for PT)

• Dose to larynx (median mean dose, in Gy)

3D-CRT: 2.3 Gy

VMAT: 11.1 Gy

PT: 1.8 Gy

MF: 37.1 Gy

P < 0.0001

Vergleich VMAT vs 3DCRT or PT: p<0.0001

• Dose to pharynx (median mean dose, in Gy)

3D-CRT: 1.7 Gy

VMAT: 5.1 Gy

PT: 1.3 Gy

MF: 23.8 Gy

P < 0.0001

• Dose to parotid glands (median mean dose, in Gy)

ipsilateral

3D-CRT: 0.5 Gy

VMAT: 0.8 Gy

PT: 0.01 Gy

MF: 32.3 Gy

P < 0.0001

Vergleich 3CRT vs VMAT (p=0.75) or PT (p=0.02)

Contralateral

3D-CRT: 0.1 Gy

VMAT: 0.2 Gy

PT: 0.0 Gy

MF: 27.4 Gy

P < 0.0001

• Dose to submandibular gland (median mean dose, in Gy)

Ipsilateral

3D-CRT: 2.4 Gy

VMAT: 3.8 Gy

PT: 0.7 Gy

Contralateral

3D-CRT: 0.1 Gy

VMAT: 0.4 Gy

PT: 0.0 Gy

• Study Duration: not reported
• Follow-up: not applicable
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: Rigshospitalet Scientific Research Committee, Copenhagen, Denmark.
• Other limitations: simulation study

(Voong, McSpadden et al. 2014)

Case series

4

n = 9

Recruitment period: not reported

Inclusion Criteria:

• Female patients
• Early stage HL with mediastinal involvement
• Previously treated with 4-6 cycles of ABVD

Exclusion Criteria:

• Bilateral axillary involvement

Baseline characteristics:

• Age: not reported
• Stage: early-stage
• Sex: 9 female

intensity modulated radiotherapy (IMRT)

conventional anteroposterior and posteroanterior directed photo beam (AP-PA)

• Planned target volume (PTV)
• Organ dose

• PTV dose (mean)

IMRT: 31.39 Gy
AP-PA: 32.02 Gy
P=0.01

• Organ dose (mean)
• Right breast

IMRT: 2.28 Gy

AP-PA: 1.92 Gy

Difference: 0.36, P=0.26

• Left breast

IMRT: 2.42 Gy

AP-PA: 2.38 Gy

Difference: 0.04, P=0.41

• Right ventricle

IMRT: 10.25

AP-PA: 12.16

Difference: -1.91, p=0.09

• Left ventricle

IMRT: 4.13

AP-PA: 7.72

Difference: -3.59, p=0.02

• Left anterior descending artery

IMRT: 10.44

AP-PA: 14.46

Difference: -4.02, p=0.02

• Heart

IMRT: 11.52 Gy

AP-PA: 14.26 Gy

Difference: -2.74, P=0.01

• Total lung

IMRT: 9.25 Gy

AP-PA: 11.31 Gy

Difference: -2.06, P=0.01

• Spinal cord

IMRT: 17.16 Gy

AP-PA: 21.93 Gy

Difference: -4.77, P=0.01

• Study Duration: not reported
• Follow-up: not applicable
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: “Cancer Center Support (core) Grant CA016672 to The University of Texas MD, Anderson Cancer Center.”
• Other limitations: treatment planning study, simulation

(Zeng, Plastaras et al. 2016)

n = 10

Recruitment: not reported

Inclusion criteria:

• Diagnosis of mediastinal lymphoma
• Treated with DS proton therapy
• at least two 4D verification CT scans

Exclusion criteria:

• Not reported

Baseline characteristics:

• Age (median): not reported
• Stage: not reported
• Not reported

Proton pencil beam scanning (PBS)

Proton double scattering (DS)

intensity-modulated radiotherapy (IMRT)

3-dimensional conformal radiotherapy (3D-CRT)

• Internal target volume coverage
• Dose reduction to lungs
• Dose to heart
• Dose to spinad cord
• Dose to breasts

• Internal target volume coverage (D98%)

PBS: 97.0% (97.0-98.6)%
DS: 97.0% (97.0-97.0)%
IMRT: 97.0% (97.0-97.0)%
3D-CRT: 97% (97.0-97.0)%

• Dose to lungs (median mean dose, 95% CI, in Gy(RBE)

PBS: 5 (2-9)
DS: 6 (3-11)*
IMRT: 9 (4-12)*
3D-CRT: 11 (6-18)*

• Dose to heart (median mean dose, 95% CI, in Gy(RBE)

PBS: 5.8 (0.4-15.9)
DS: 7.4 (0.7-16.3)*
IMRT: 10.4 (0.9-17.5)*
3D-CRT: 12.7 (1.9-25.8)*

• Dose to spinal cord (median maximum dose, 95% CI, in Gy(RBE)

PBS: 14 (1-23)
DS: 26 (10-33)*
IMRT: 27 (24-28)*
3D-CRT: 32 (30-34)*

• Dose to breasts (median mean dose, 95% CI, in Gy(RBE)

PBS: 0.5 (0.5-3.1)
DS: 0.6 (0.6-3.2)
IMRT: 1.0 (0.8-2.7)*
3D-CRT: 1.0 (1.0-3.7)*

• Study Duration: not reported
• Follow-up: see above
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: This work was supported by Ion Beam Applications S.A., Louvain-la-Neuve, Walloon Brabant, Belgium (IBA). The authors would like to thank Olivier De Wilde and Guillaume Janssens from IBA for their contribution.
• Other limitations: simulation study

Prospektive Studien

Geplantes Zielvolumen

-

-

-

+

-

⊕⊝⊝⊝ very low

Organdosis

-

-

-

+

-

⊕⊝⊝⊝ very low

(Kriz, Spickermann et al. 2015)

n = 11

Recruitment: 2014 - 2016

prescription dose was 30.6 Gy as mean PTV dose

Inclusion criteria:

• de novo HL in early favourable and early unfavourable stages
• mediastinal involvement and involvement of hilar, supra/infraclavicular and/or cervical lymph nodes

Exclusion criteria:

• Not reported 

Baseline characteristics:

• Age (median): 22 years (range: 18-68)
• Stage: early F & U

5 women, 6 men

intensity-modulated radiotherapy (IMRT), two different plans

Involved Field Radiotherapy (IF-RT).

- one in DIBH

- one in FB

For each patient 12 different treatment plans were calculated

standard 

RT (APPA) 

3D-RT

Involved Site

Radiotherapy (IS-RT)

- one in DIBH

- one in FB

• Planning target volume
• Dose to heart
• Dose to lung
• Dose to left breast
• Dose to right breast
• Dose to oesophagus
• Dose to spinal cord
• External dose (skin)

Involved-site

• Planning target volume (Mean dose Dmean, %, sd)

DIBH APPA: 101.05 (1.04)

DIBH IMRT-5F: 101.10 (1.63)

DIBH IMRT-7F: 100.34 (0.76)

FB APPA: 100.22 (0.58)

FB IMRT-5F: 99.85 (0.61)

FB IMRT-7F: 99.17 (0.55) 

• Dose to heart (average mean dose, sd, in Gy)

DIBH APPA: 3.97 (4.47)

DIBH IMRT-5F: 4.08 (4.54)

DIBH IMRT-7F: 4.41 (5.19)

FB APPA: 5.74 (5.76)

FB IMRT-5F: 5.88 (5.83)

FB IMRT-7F: 15.43 (4.24)

• Dose to lung (average mean dose, sd, in Gy)

DIBH APPA: 5.87 (4.10)

DIBH IMRT-5F: 6.54 (3.52)

DIBH IMRT-7F: 7.18 (2.80)

FB APPA: 9.88 (4.22)

FB IMRT-5F: 7.69 (3.59)

FB IMRT-7F: 8.25 (2.96)

• Dose to left breast (average mean dose, sd, in Gy)

DIBH APPA: 2.01 (3.03)

DIBH IMRT-5F: 2.44 (2.79)

DIBH IMRT-7F: 3.23 (2.35)

FB APPA: 2.80 (3.98)

FB IMRT-5F: 2.82 (3.56)

FB IMRT-7F: 3.38 (3.06)

• Dose to right breast (average mean dose, sd, in Gy)

DIBH APPA: 0.57 (0.37)

DIBH IMRT-5F: 1.19 (0.52)

DIBH IMRT-7F: 2.54 (0.94)

FB APPA: 0.77 (0.92)

FB IMRT-5F: 1.22 (1.08)

FB IMRT-7F: 2.30 (1.53)

• Dose to oesophagus (average mean dose, sd, in Gy)

DIBH APPA: 16.32 (5.54)

DIBH IMRT-5F: 15.76 (4.91)

DIBH IMRT-7F: 15.95 (4.91)

FB APPA: 15.67 (4.47)

FB IMRT-5F: 15.43 (4.24)

FB IMRT-7F: 15.92 (4.45) 

• Dose to spinal cord (average mean dose, sd, in Gy)

DIBH APPA: 32.08 (0.66)

DIBH IMRT-5F: 24.74 (2.41)

DIBH IMRT-7F: 17.49 (1.62)

FB APPA: 31.46 (0.30)

FB IMRT-5F: 24.31 (2.25)

FB IMRT-7F:17.31 (1.18)

• External dose (average mean dose, sd, in Gy)

DIBH APPA: 2.26 (1.28)

DIBH IMRT-5F: 2.39 (1.25)

DIBH IMRT-7F: 2.59 (1.11)

FB APPA: 2.16 (1.21)

FB IMRT-5F: 2.29 (1.18)

FB IMRT-7F: 2.41 (1.07)

Involved-field

• Planning target volume (Mean dose Dmean, %, sd)

DIBH APPA: 101.70 (117)

DIBH IMRT-5F: 100.37 (0.89)

DIBH IMRT-7F: 100.81 (0.71)

FB APPA: 100.80 (0.87)

FB IMRT-5F: 100.14 (0.9)

FB IMRT-7F: 99.95 (0.72)

• Dose to heart (average mean dose, sd, in Gy)

DIBH APPA: 12.05 (9.81)

DIBH IMRT-5F: 11.17 (8.79)

DIBH IMRT-7F: 10.74 (8.08)

FB APPA: 12.60 (9.73)

FB IMRT-5F: 13.84 (9.0)

FB IMRT-7F: 14.31 (9.49) 

• Dose to lung (average mean dose, sd, in Gy)

DIBH APPA: 8.73 (4.69)

DIBH IMRT-5F: 9.93 (4.46)

DIBH IMRT-7F: 10.64 (3.94)

FB APPA: 9.91 (5.23)

FB IMRT-5F: 12.14 (5.1)

FB IMRT-7F: 13.00 (5.00)

• Dose to left breast (average mean dose, sd, in Gy)

DIBH APPA: 3.80 (4.26)

DIBH IMRT-5F: 5.03 (4.08)

DIBH IMRT-7F: 7.37 (4.38)

FB APPA: 4.47 (4.43)

FB IMRT-5F: 5.01 (4.1)

FB IMRT-7F: 7.10 (3.48) 

• Dose to right breast (average mean dose, sd, in Gy)

DIBH APPA: 1.37 (0.67)

DIBH IMRT-5F: 2.75 (1.23)

DIBH IMRT-7F: 5.50 (2.29)

FB APPA: 1.50 (1.18)

FB IMRT-5F: 2.41 (1.5)

FB IMRT-7F: 4.90 (2.30) 

• Dose to oesophagus (average mean dose, sd, in Gy)

DIBH APPA: 23.26 (6.45)

DIBH IMRT-5F: 22.35 (5.98)

DIBH IMRT-7F: 22.28 (6.22)

FB APPA: 23.28 (5.78)

FB IMRT-5F: 23.17 (5.9)

FB IMRT-7F: 23.21 (6.47)

• Dose to spinal cord (average mean dose, sd, in Gy)

DIBH APPA: 30.71 (6.60)

DIBH IMRT-5F: 25.28 (4.97)

DIBH IMRT-7F: 19.17 (3.57)

FB APPA: 30.87 (4.84)

FB IMRT-5F: 27.48 (3.0)

FB IMRT-7F: 21.67 (4.12)

• External dose (average mean dose, sd, in Gy)

DIBH APPA: 3.94 (1.71)

DIBH IMRT-5F: 4.16 (1.82)

DIBH IMRT-7F: 4.44 (1.69)

FB APPA: 3.62 (1.38)

FB IMRT-5F: 4.04 (1.6)

• FB IMRT-7F: 4.32 (1.63)

• Study Duration: not reported
• Follow-up: not applicable
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: not reported
• Other limitations: simulation study, each possible treatment plan for each patient

(Paumier, Ghalibafian et al. 2012)(dosimetric benefits)

doi:10.1016/j.ijrobp.2011.05.015

n = 28

Recruitment: not reported

clinical target volume was defined according to the INRT

Inclusion criteria:

• Early-stage (I-II) HL involving the mediastinum
• Consecutive patients 

Exclusion criteria:

• Not reported

 Baseline characteristics:

• Age (median): not reported
• Stage: early
• Sex: not reported

Free-breathing IMRT (DIBH)

Deep-inspiration

breath-hold IMRT (FB)

• dosimetric parameters

 coronary dose

 heart dose

 lung dose

• Clinical target volume (CTV, 95% CI)

FB: 290 (240-350)

DIBH: 270 (220-320)

Difference: 7% (p=0.0007)

• Planning target volume (PTV, 95% CI)

FB: 750 (640-850)

DIBH: 720 (620-820)

Difference: 4% (n.s.)

• Mean coronary dose (95% CI, in Gy)

FB: 18.2 (15.9-20.6)

DIBH: 15.2 (12.2-17.9)

Difference: 16% (p=0.0002)

• Mean heart dose (95% CI, in Gy)

FB: 8.4 (6.1-10.7)

DIBH: 7.1 (4.7-9.6)

Difference: 15%, p=0.002)

• Mean lung dose (95% CI, in Gy)

FB: 11.8 (10.6-12.9)

DIBH: 9.4 (8.3-10.4)

Difference: 20% (p<0.0001)

• Study Duration: not reported
• Follow-up: not applicable, treatment planning study
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: Not reported
• Other limitations: time point for IMRT and DIBH OS and PFS are NOT comparable! 5-year vs. 3-year OS and PFS reported

(Rechner, Maraldo et al. 2017)

n = 22

Recruitment: 2010 - 2012

Inclusion criteria:

• Diagnosis of HL
• Age ≥ 18
• Mediastinal RT expected to be part of the treatment
• Patient able to comply with the procedures
• Signed consent

Exclusion criteria:

• Not reported

Baseline characteristics:

• Age (median): 30 years (range 18-62 years)
• Stage: IA:1; IIA: 14, IIAE: 1; IIB: 6
• 8 male, 14 female

proton therapy

- deep inspiration breath hold

- free breathing

intensity modulated radiation therapy (IMRT)

- deep inspiration breath hold

- free breathing

• Heart dose
• Valve dose
• Valve dose EQD2 (equivalent dose in 2 Gy fractions)
• LADCA dose
• Lung dose
• Breast dose

• Heart dose (median, range, in Gy)

IMRT – FB: 8.0 (0.1 – 23.2)

IMRT – DIBH: 3.6 (0.1-17.3)

Proton – FB: 6.1 (0.3-17.3)

Proton DIBH: 3.7 (0.3-13.6)

• Valve dose (median, range, in Gy)

IMRT – FB: 21.0 (0.3-30.0)

IMRT – DIBH: 13.4 (0.2-28.8)

Proton – FB: 16.7 (0.3-30.2)

Proton DIBH: 9.5 (0.3-29.1)

• Valve dose EQD2 (equivalent dose in 2 Gy fractions) (median, range, in Gy)

IMRT – FB: 15.8 (0.2-29.6)

IMRT – DIBH: 7.8 (0.1-29.6)

Proton – FB: 11.3 (0.1-30.0)

Proton DIBH: 6.5 (0.1-30.0)

• LADCA dose (median, range, in Gy)

IMRT – FB: 7.7 (0.1-29.5)

IMRT – DIBH: 4.7 (0.1-24.5)

Proton – FB: 5.2 (0.3-29.9)

Proton DIBH: 2.9 (0.3-24.9)

• Lung dose (median, range, in Gy)

IMRT – FB: 9.8 (1.8-17.2)

IMRT – DIBH: 8.0 (1.4-12.6)

Proton – FB: 7.0 (0.8-12.8)

Proton DIBH: 5.7 (0.9-10.3)

• Breast dose (median, range, in Gy)

IMRT – FB: 4.3 (0.1-14.4)

IMRT – DIBH: 4.6 (0.2-12.5)

Proton – FB: 1.4 (0.3-6.3)

Proton DIBH: 1.6 (0.3-4.1)

• Study Duration: not reported
• Follow-up: see above
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: Nils Patrik Brodin acknowledges support from the NIH/National Center for Advancing Translational Science (NCATS) Einstein-Montefiore CTSA Grant Number KL2TR001071 and UL1TR001073. Marianne Camille Aznar acknowledges support from Cancer Research UK (grant number C8225/A21133). Laura Ann Rechner was partially funded by a grant from Varian Medical Systems for this project.
• Other limitations: simulation study

Prospektive Studien

Geplantes Zielvolumen

-

-

-

+

-

⊕⊝⊝⊝ very low

Organdosis

-

-

-

+

-

⊕⊝⊝⊝ very low

(Chera, Rodriguez et al. 2009)

n = 9

Inclusion Criteria:

• Stage IIA – IIB HL of the neck and/or mediastinum
• Treated at the university of Florida between 2005 and 2007

Exclusion Criteria:

• None

Baseline characteristics:

• Age: not reported
• Stage: IIA – IIB
• Recurrence status: not reported

3D proton radiotherapy (3D-PRT)

With a single anteroposterior-oriented beam centered on the PTV, brass aperture margin 1 cm around the PTV
n = 9

Conventional radiotherapy (CRT)
with a pair of parallel-opposed 6- or 18-megavoltage photon beams centered on the PTV
n = 9

Intensity-modulated radiotherapy (IMRT)
with 5 equally spaced (72°) beams centered on the PTV
n = 9

• Quality of target coverage (mean doses, relative and absolute volumes receiving radiation)

• Mean dose (CGE/Gy) for body:
  CRT: 2.47 (1.05)
  IMRT: 2.66 (1.21)
  3D-PRT: 1.12 (0.75) 
• Mean dose (CGE/Gy) for lung:
  

CRT: 4.83 (3.67)
IMRT: 5.38 (3.85)
3D-PRT: 3.04 (2.88)

• Mean dose (CGE/Gy) for breast:
  

CRT: 1.94 (1.95)
IMRT: 3.74 (3.43)
3D-PRT: 1.59 (1.73) 

• Mean dose (CGE/Gy) for thyroid:
  

CRT: 7.09 (6.80)
IMRT: 9.07 (8.61)
3D-PRT: 4.65 (4.94)

• Safety/AEs: not reported
• QoL: not reported

• Study Duration: not reported
• Follow-up: none
• ITT: not reported
• Randomisation: no
• Blinding: no
• Funding: not reported
• Other limitations: none detected

(Eley, Friedrich et al. 2016)

n = 9

Recruitment: not reported

Inclusion criteria:

• Selection of 9 records of female stage II HL patients and bulky disease localised above the diaphragm 

Exclusion criteria:

• Not reported

Baseline characteristics:

• Females
• Stage: stage II

RBES-weighted dose from proton treatment plans

RBES-weighted dose from carbon treatment plans

• Dose to breast
• Dose to heart
• Dose to lung
• Dose to Esophagus
• Dose to cord
• Predicted secondary cancer risks

• Dose to breast (mean, SE)
  Proton (Dp): 3.4 (0.85)
  Carbon (Dc): 2.15 (0.65)
  Ratio Dc/DP: 0.63, p=0.004

• Dose to heart
  

Proton (Dp): 6.06 (1.51)
Carbon (Dc): 4.42 (1.32)
Ratio Dc/DP: 0.73, p=0.004

• Dose to lung
  

Proton (Dp): 6.45 (0.98)
Carbon (Dc): 4.80 (0.76)
Ratio Dc/DP: 0.74, p=0.004 

• Dose to esophagus
  

Proton (Dp): 11.10 (2.46)
Carbon (Dc): 9.79 (2.32)
Ratio Dc/DP: 0.88, p=0.18

• Dose to cord
  

Proton (Dp): 0.40 (0.11)
Carbon (Dc): 0.84 (0.16)
Ratio Dc/DP: 2.1, p=0.508

• Study Duration: retrospective records
• Follow-up: not applicable
• ITT: no
• Randomisation: no, each treatment plan for every person
• Blinding: no
• Funding: not reported
• Other limitations: non-RCT treatment planning study

(Hoppe, Flampouri et al. 2012)

n = 10

phase II study developing 3 separate optimised treatment plans for each patient

Inclusion Criteria:

• Stage IA – IIIB mediastinal HL
• Evaluated at the university of Florida between June 2009 and November 2010
• At least 6 years old
• Initial prechemotherapy staging PET-CT
• Either complete response or partial response to standard chemotherapy and could start INRT within 8 weeks of completing chemotherapy

Exclusion Criteria:

• None

Baseline characteristics:

• Age: not reported
• Stage: IIA – IIB
• Recurrence status: not reported

Proton therapy (De Bruin, Huisbrink et al.)
n = 10

3D conformal radiotherapy (3D-CRT)

n = 10

Intensity-modulated radiotherapy (IMRT)
n = 10

• Dose-volume data: V4 (total organ exposed to 4 Gy or higher) and mean dose
• Dose reduction to organs at risk (OARs)

• Body V4: median
  3D-CRT: 5739.0 cm³
  IMRT: 6989.0 cm³
  PT: 3420.0 cm³
• Body mean dose: median
  3D-CRT: 9.5 Gy
  IMRT: 7.7 Gy
  PT: 4.1 CGE
  PT vs. 3D-CRT: -0.59 (p=0.002)
  PT vs. IMRT: -0.53 (p=0.002)
• Heart V4: median
  3D-CRT: 79.1%
  IMRT: 70.6%
  PT: 37.9%
• Heart mean dose: median
  3D-CRT: 19.4 Gy
  IMRT: 12.2 Gy
  PT: 8.9 CGE
  PT vs. 3D-CRT: -10.4 Gy (p=0.002)
  PT vs. IMRT: -4.3 (p=0.002)
•  Lung V4: median
  3D-CRT: 56.2%
  IMRT: 65.4%
  PT: 33.7%
• Lung mean dose: median
  3D-CRT: 13.2 Gy
  IMRT: 10.6 Gy
  PT: 7.1 CGE
  PT vs. 3D-CRT: -5.5 (p=0.002)
  PT vs. IMRT: -3.1 (p=0.002)
• Breasts V4: median
  3D-CRT: 23.3%
  IMRT: 37.4%
  PT: 21.3%
• Breasts mean dose: median
  3D-CRT: 5.4 Gy
  IMRT: 5.5 Gy
  PT: 4.6 CGE
  PT vs. 3D-CRT: -0.9 (p=0.0078)
  PT vs. IMRT: -1.4 (p=0.0078)
• Esophagus V4: median
  3D-CRT: 77.1%
  IMRT: 70.1%
  PT: 50.4%
• Esophagus mean dose: median
  3D-CRT: 22.6 Gy
  IMRT: 17.2 Gy
  PT: 17.0 CGE
  PT vs. 3D-CRT: -8.3 (p=0.0038)
  PT vs. IMRT: -2.8 (p=0.0195)
• Thyroid V4: median
  3D-CRT: 77.5%
  IMRT: 98.8%
  PT: 66.6%
• Thyroid mean dose: median
  3D-CRT: 18.8 Gy
  IMRT: 19.3 Gy
  PT: 14.7 CGE
  PT vs. 3D-CRT: -4.1 (p=0.002)
  PT vs. IMRT: -2.7 (p=0.0742)