Methods

Randomised controlled trial with two arms:

• Chemotherapy alone arm and chemotherapy plus radiotherapy arm

Recruitment period:

• 1970s, exact period unclear

• 55 patients allocated; exact number per arm not reported

• 37 patients evaluated: 18 patients in chemotherapy alone arm and 19 patients in chemotherapy plus radiotherapy arm

Baseline patient's characteristics described

Median follow‐up time:

• 22 months

No ITT analysis; more than 10% of the enrolled patients not evaluated

Conducted by the Cancer and Leukemia Group B (CALGB), USA

Participants

Inclusion criteria:

• Patients with histologically documented, previously untreated, poor prognosis pathological stage I and II; poor prognosis was defined as symptom class B, mixed cellularity or lymphocyte depleted histology, a large mediastinal mass, or age > 40 years

Exclusion criteria:

• Not reported

PS I, II:

• Chemotherapy alone: 1, 17

• Chemotherapy plus radiotherapy: 6, 13

Prognostic features: not reported

Mean age:

• Chemotherapy alone: 24 years

• Chemotherapy plus radiotherapy: 30 years

Gender:

• Chemotherapy alone: 6 male, 12 female

• Chemotherapy plus radiotherapy: 14 male, 5 female

Baseline patient's characteristics: more male patients in chemotherapy plus radiotherapy arm; more patients with mediastinal mass in chemotherapy alone arm

Histopathologic diagnosis: according to Rye modification of Lukes and Butler classification

Country:

• USA

Interventions

• Chemotherapy alone: 6 cycles of CVPP (cyclophosphamide (75 mg/m² orally, day 1), vinblastine (4mg/m² intravenous, days 1 and 8), procarbazine (100 mg/m² orally, days 1‐14), prednisone (40 mg/m² orally, days 1‐14)); repeated every 14 days

• Chemotherapy plus radiotherapy: same chemotherapy with involved‐field radiotherapy; dose of radiotherapy not reported; radiotherapy delivered before chemotherapy

• No additional treatment

Outcomes

• Overall survival (reported)

• Complete response (reported)

Notes

• Response documented after two cycles of chemotherapy

• Source of funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly allocated".

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding (performance bias and detection bias)
Overall survival

Low risk

Patients not blinded. No information about blinding of the assessor. This is judged not to be a source of bias for overall survival.

Blinding (performance bias and detection bias)
Other outcomes

Unclear risk

Patients not blinded. No information about blinding of the assessor.

Incomplete outcome data (attrition bias)
All outcomes

High risk

22 months OS and response outcome: 18/55 missing from the outcome analysis; no information per study arm. This trial was considered not to have performed an ITT analysis in the subgroup analysis.

Selective reporting (reporting bias)

Unclear risk

Dates of relapse and deaths are given. Dates of progression not given nor information about censoring. No time‐ to‐ event outcomes calculated. No study protocol identified, therefore unclear if all the planned outcomes are reported.

Other bias

Unclear risk

Insufficient information to assess whether an important risk of bias exists.

Methods

Randomised controlled trial with three arms:

• Comparison of three radiation doses; 36 Gy involved‐field radiotherapy, 20 Gy involved‐field radiotherapy and no radiotherapy in patients that achieved complete response (CR) after six cycles of EBVP

Recruitment period

• September 1998 to May 2004

• 784 patients enrolled

• 13 patients not evaluable before randomisation (6 refusals, 3 protocol violations, 4 unspecified)

• 578 patients randomised to three radiation doses

• 578 patients evaluated

Baseline patient's characteristics not reported (abstract publication)

Median follow‐up:

• 51 months (range 14 to 81)

ITT analysis

Conducted by EORTC (European Organization for Research and Treatment of Cancer) and GELA (Groupe d'Etude des Lymphomes de l'Adulte); 111 institutions from 10 European countries involved

Participants

Inclusion criteria:

• Adults with supradiaphragmatic CS I‐II Hodgkin lymphoma and favourable features (age < 50, CS I‐II, symptoms class A + ESR < 50 or symptoms class B + ESR < 30 and MT ratio < 0.35)

Exclusion criteria:

• Not reported

Mean age (range):

• 31 (15 to 49)

Gender:

• 55% male; 45% female

CS: patients with CS I‐II without bulky disease

Prognostic features: all included patients with favourable risk factors

Histopathologic diagnosis: not reported

Country:

• Europe

Interventions

• Chemotherapy alone: 6 cycles of EBVP (epirubicin (70 mg/m² intravenous, day 1), bleomycin (10 mg/m² intravenous/intramuscular, day 1), vinblastine (6 mg/m² intravenous, day 1), prednisone (40 mg/m² orally, day 1‐5)); repeated after every 21 days

• Chemotherapy plus radiotherapy: same chemotherapy before randomisation with 36 Gy involved‐field radiotherapy or 20 Gy involved‐field radiotherapy

• No additional treatment

Outcomes

• Overall survival (reported); observation time 4 years

• Disease‐free survival (reported, Table 2)

Notes

• Inclusion of patients in no radiotherapy arm was stopped in May 2002 because stopping rules were met that is > 20% events occurred

• Hazard ratio estimate is based on the full group receiving additional radiotherapy and not only those patients up to the time the no radiotherapy arm was stopped

• Source of funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Patients were randomly allocated. No further information available.

Allocation concealment (selection bias)

Unclear risk

No information available from the publications.

Blinding (performance bias and detection bias)
Overall survival

Low risk

Patients not blinded (not expected due to the treatment with radiotherapy). No information about blinding of the assessor. This is judged not to be a source of bias for overall survival.

Blinding (performance bias and detection bias)
Other outcomes

Unclear risk

Patients and physicians not blinded (not expected due to the treatment with radiotherapy). No information about blinding of the assessor.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No withdrawals and protocol violations after randomisation reported. Analysis was performed on ITT basis and all randomised patients were included in the analysis.

Selective reporting (reporting bias)

Unclear risk

Rationale for the use of disease‐free survival not described. However all patients are in CR at the time of randomisation. Disease‐free survival should therefore be equivalent to progression‐free survival. Other progression outcomes that are more prone to bias are not used and not reported. Study protocol available, no planed outcomes stated.

Other bias

High risk

The chemotherapy alone arm ended early due to stopping rules. Unfortunately it was not possible to receive the data on patients receiving additional radiotherapy only up to the date the chemotherapy alone arm was stopped. This is known to increase the effect estimate of trials. In addition the data are preliminary.

Methods

See H10U

Participants

See H10U

Interventions

See H10U

Outcomes

See H10U

Notes

See H10U

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Minimization technique was used...".

Allocation concealment (selection bias)

Low risk

"Centrally randomly assigned to receive either...".

Blinding (performance bias and detection bias)
Overall survival

Low risk

Although the study is likely not to be blinded, this does not affect the outcome OS.

Blinding (performance bias and detection bias)
Other outcomes

Low risk

The study did not address blinding of participants or physicians. Regarding the study design it is likely that there was no blinding. However, the outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data.

Selective reporting (reporting bias)

High risk

Study protocol available. Not all of the study’s pre‐specified secondary outcomes reported:

• Event‐free survival

• Overall survival

• Long‐term toxicity in terms of secondary malignancies, cardiovascular events, and pulmonary events

• Response

Other bias

Unclear risk

Insufficient information to assess whether an important risk of bias exists.

Methods

Randomised controlled trial with two main groups (favourable (F) vs unfavourable (U) disease), each with two subgroups, one consisting of two arms, the other of one arm. Comparison of three treatment models in total. PET measurement after randomisation

Subgroups: experimental arm (PET‐adapted therapy) vs standard treatment

• Experimental:

  • F:

    • PET‐negative: chemotherapy alone

    • PET‐positive: chemotherapy plus radiotherapy

  • U:

    • PET‐negative: chemotherapy alone

    • PET‐positive: chemotherapy plus radiotherapy

• Standard treatment:

  • F: chemotherapy plus radiotherapy

  • U: chemotherapy plus radiotherapy

The PET‐positive arms are not considered in this review

Recruitment period:

• October 2006 to July 2009

• 1952 patients allocated

• 1137 patients randomised

• 1124 patients analysed (11 patients did not complete the first two cycles of ABVD or had no early PET scan performed, and for two patients, no validated data were available)

Favourable:

• PET negative: chemotherapy alone: 193; chemotherapy plus radiotherapy: 188

• PET positive: chemotherapy plus radiotherapy: 27; chemotherapy plus radiotherapy: 33

Unfavourable:

• PET negative: chemotherapy alone: 268; chemotherapy plus radiotherapy: 251

• PET positive: chemotherapy plus radiotherapy: 76; chemotherapy plus radiotherapy: 88

• Patients excluded: N = 13 (did not complete first 2 cycles ABVD / no PET/no validated PET)

Baseline patient's characteristics described

Median follow‐up time:

• 13.2 months (1.1 year)

No ITT analysis

Conducted by the European Organisation for Research and Treatment of Cancer (EORTC)

Participants

Inclusion criteria:

• Previously untreated histologically proven classic HL

• Supradiaphragmatic Ann Arbor stage I and II

• Between 15 and 70 years old

• WHO performance status of 0 to 3

• Written informed consent

Exclusion criteria:

• No severe cardiac, pulmonary, neurologic, psychiatric, or metabolic disease

• No unstable diabetes mellitus

• No other malignancies within the past 5 years except for basal cell skin cancer or adequately treated carcinoma in situ of the cervix

• No known HIV infection

• No psychological, familial, sociological, or geographical condition that would preclude study compliance

Mean age (range):

• 31 years (15 to 70 years)

Gender:

• 51% male

CS I, II:

• Stage reported for PET‐negative‐patients only

Country:

• Europe

Interventions

Experimental:

• F: 2 cycles of ABVD + PET

  • PET‐negative: + 2 cycles of ABVD

  • PET‐positive: + 2 cycles of BEACOPPesc + 30 Gy (+6 Gy) involved node radiotherapy

• U: 2 cycles of ABVD + PET

  • PET‐negative: + 4 cycles of ABVD

  • PET‐positive: + 2 cycles of BEACOPPesc + 30 Gy (+6 Gy) involved node radiotherapy

Standard treatment:

• F: 3 cycles of ABVD + 30 Gy (+6 Gy) involved node radiotherapy

• U: 4 cycles of ABVD + 30 Gy (+6 Gy) involved node radiotherapy

FDG‐PET scans:

• PET examination after two cycles of chemotherapy

• Evaluation by the various central reviewers

  • Additional blind PET review on all patients with an event and an equal number of randomly selected patients without an event

Outcomes

Primary outcome:

• Progression‐free survival (reported)

Secondary outcomes:

• Event‐free survival (not reported)

• Overall survival (not reported)

• Long‐term toxicity, in terms of secondary malignancies, cardiovascular events, and pulmonary events (not reported)

• Response (not reported)

Notes

Source of funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Minimization technique was used...".

Allocation concealment (selection bias)

Low risk

"Centrally randomly assigned to receive either...".

Blinding (performance bias and detection bias)
Overall survival

Low risk

Although the study is likely not to be blinded, this does not affect the outcome OS.

Blinding (performance bias and detection bias)
Other outcomes

Low risk

The study did not address blinding of participants or physicians. Regarding the study design it is likely that there was no blinding. However, the outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data.

Selective reporting (reporting bias)

High risk

Study protocol available. Not all of the study’s pre‐specified secondary outcomes reported:

• Event‐free survival

• Overall survival

• Long‐term toxicity in terms of secondary malignancies, cardiovascular events, and pulmonary events

• Response

Other bias

Unclear risk

Insufficient information to assess whether an important risk of bias exists.

Methods

Randomised controlled trial with three arms:

Chemotherapy alone arm and chemotherapy plus radiotherapy or radiotherapy alone arm

• • F: chemotherapy alone versus radiotherapy alone

  • U: chemotherapy alone versus chemotherapy plus radiotherapy

Recruitment period:

• January 1994 to April 2002

• 405 patients enrolled

• 405 patients randomised:

  • Chemotherapy alone: 199

  • Chemotherapy plus radiotherapy or radiotherapy alone: 206

• 399 patients evaluated:

  • Chemotherapy alone:

    • F: 59

    • U: 137

  • Chemotherapy plus radiotherapy or radiotherapy alone:

    • F: 64 (radiotherapy alone)

    • U: 139 (chemotherapy plus radiotherapy)

Baseline patient characteristics described

Median follow‐up time:

• 11.3 years from randomisation

ITT‐Analysis

Conducted by National Cancer Institute of Canada Clinical Trials Group (NCIC‐CTG) in 1994. Collaboration with the Eastern Cooperative Oncology Group (ECOG) in 1996

Participants

Inclusion criteria:

• Patients with a confirmed diagnosis of limited‐stage Hodgkin lymphoma without previous treatment

• Clinical or pathological stage IA and IIA and absence of bulky disease (mediastinal mass ≤ 0.33 of the maximum chest wall diameter or any mass ≤ 10 cm in its largest diameter)

• Isolated subdiaphragmatic disease were eligible provided that all evidence of disease was confined to the iliac, inguinal and/or femoral regions

Exclusion criteria:

• Intra‐abdominal or splenic disease

• Low‐risk limited‐stage Hodgkin’s lymphoma

• Evidence of lung or cardiac dysfunction, or other general medical problems that would preclude administration of either of the assigned therapies

• Abnormal baseline laboratory values of hematologic, renal or liver function, a known positive antibody test for the human immunodeficiency virus, or a prior or concurrent malignancy

• Staging laparotomy

399 patients included in the analyses

• Chemotherapy alone:

• • F: 59

  • U: 137

• Chemotherapy plus radiotherapy or radiotherapy alone:

• • F: 64

  • U: 139

Patients not receiving therapy as randomised (41 of 399):

• Chemotherapy alone: 16 (8 also received radiotherapy, 3 received less than 4 cycles of ABVD, 2 received other chemotherapy, 3 treatment unknown)

• Chemotherapy plus radiotherapy/radiotherapy alone: 25

  • F: 11 (9 also received chemotherapy, 2 received less than protocol radiation)

  • U: 14 (1 received less than 2 cycles of ABVD, 13 received less than protocol radiation)

Patients excluded before randomisation: 6

Mean age:

• Chemotherapy alone: 35 years

• Chemotherapy plus radiotherapy/radiotherapy alone: 36.7 years

Gender:

• Chemotherapy alone: 54% male

• Chemotherapy plus radiotherapy/radiotherapy alone: 57% male

Country:

• Canada, Italy, UK

Interventions

Chemotherapy alone:

• Patients with favourable and unfavourable risk profile: 4 cycles of ABVD, with restaging of the disease after 2 and 4 cycles of therapy

• Patients with a complete remission or an unconfirmed complete remission after 2 treatment cycles received a total of 4 cycles of ABVD

• Patients without a complete remission or an unconfirmed complete remission after their second cycle received 6 cycles of ABVD

Chemotherapy plus radiotherapy:

• Patients with favourable risk profile: subtotal nodal radiation therapy alone

• Patients with an unfavourable risk profile: 2 cycles of ABVD followed by subtotal nodal radiation therapy (35Gy in 20 fractions (daily))

Outcomes

Primary outcome:

• Overall survival (reported)

Secondary outcomes:

• Event free survival (reported)

• Freedom from progression (reported)

• Complete response rate (not reported)

• Second disease progression rate (not reported)

• Cause‐specific survival rate (not reported)

• Quality of Life (not reported)

• Treatment‐related toxicity (not reported)

Notes

• The NCIC Clinical Trials Group was supported by funds from the Canadian Cancer Society, through grants from the National Cancer Institute of Canada and the Canadian Cancer Society Research Institute, and by the National Cancer Institute, National Institutes of Health; the Eastern Cooperative Oncology Group was supported by grants from the National Cancer Institute

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The HD.6 trial was a [...] randomized, controlled trial".

"The process for randomization was concealed and was performed by means of a computer‐generated random‐number sequence that was held at the central office of the NCIC Clinical Trials Group".

Allocation concealment (selection bias)

Low risk

"The process for randomization was concealed and was performed by means of a computer‐generated random‐number sequence that was held at the central office of the NCIC Clinical Trials Group".

Blinding (performance bias and detection bias)
Overall survival

Low risk

Patients not blinded. No information about blinding of the assessor. This is judged not to be a source of bias for overall survival.

Blinding (performance bias and detection bias)
Other outcomes

Unclear risk

Patients not blinded. No information about blinding of the assessor.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"All primary analyses were performed on data from the modified intention‐to‐treat population".

6 of 405 randomised patients were "subsequently considered to be ineligible on the basis of prerandomization data".

Selective reporting (reporting bias)

High risk

Study protocol available. Not all of the study’s pre‐specified secondary outcomes reported. Not all of the study’s pre‐specified secondary outcomes reported:

• Complete response rate

• Second disease progression rate

• Cause‐specific survival rate

• Quality of Life

• Treatment‐related toxicity

Other bias

High risk

41 of 399 patients not received therapy as randomised.

Methods

Randomised controlled trial with three arms:

• Chemotherapy alone arm, chemotherapy plus radiotherapy arm and radiotherapy alone arm

Recruitment period:

• 1983 to 1988

• 327 patients enrolled

• 307 patients evaluated; 99 patients in chemotherapy alone arm; 102 patients in chemotherapy plus radiotherapy arm and 106 patients in radiotherapy alone arm

• 20 patients not evaluated due to advanced stage and infradiaphragmatic involvement

• Baseline patient characteristics described

Median follow‐up time:

• 11.4 years (range 6.3 ‐ 16.5 years)

No ITT analysis; less than 10% of enrolled patients not evaluated

Conducted at Oncology Hospital, National Medical Center, Mexico

Participants

Inclusion criteria:

• Both male and female adults with clinical stage I and II (CS I and II)

• Supradiaphragmatic disease

• Presence of bulky disease

Exclusion criteria:

• Advanced stages

• Infradiaphragmatic involvement

CS I, II:

• Chemotherapy alone: 21, 78

• Chemotherapy plus radiotherapy: 22, 80

• Overall CS I 34%, CS II 66%.

Prognostic features not reported

Mean age (range):

• Chemotherapy alone: 39 (20 to 70) years

• Chemotherapy plus radiotherapy: 42 (18 to 71) years

Gender:

• Chemotherapy alone: 40 male, 59 female

• Chemotherapy plus radiotherapy: 51 male, 51 female

• Similar baseline patient's characteristics in comparison arms

• Histopathologic diagnosis: according to Rye modification of Lukes and Butler classification

Country:

• Mexico

Interventions

• Chemotherapy alone: 6 monthly cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine); dose not reported

• Chemotherapy plus radiotherapy: same chemotherapy with mantle‐field radiotherapy (MF‐radiotherapy) between third and fourth cycles of chemotherapy (sandwich technique); dose of radiotherapy: 3500‐3800 cGy in fractions of 200 to 250 cGy four to five times a week for four to six weeks

• Radiotherapy alone: EF‐radiotherapy with a dose of 3500‐3800 cGy in fraction of 200‐250 cGy four to five times a week over a period of four weeks; 106 patients from this arm not included in the review

• No additional treatment

Outcomes

• Overall survival (reported; observation time 12 year).

• Complete response (reported)

• Partial response (reported)

• Contradictory definitions of disease‐free survival (reported, see Table 2)

Notes

• Source of funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"a prospective randomised trial" No further information available.

Allocation concealment (selection bias)

Unclear risk

No information available.

Blinding (performance bias and detection bias)
Overall survival

Low risk

Patients not blinded. No information about blinding of the assessor. This is judged not to be a source of bias for overall survival.

Blinding (performance bias and detection bias)
Other outcomes

Unclear risk

Patients and physicians not blinded. No information about blinding of the assessor.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

12 years OS and tumour control outcome: 20/327 missing from the outcome analysis; no information per study arm. The authors do not give any further information about the method of analysis (e.g. ITT )

We do not believe that these few missing patients induced large bias in the analysis, the information is not available by study arm.

For subgroup analysis this trial was considered to have no ITT analysis.

Selective reporting (reporting bias)

Unclear risk

In the methods section: "Disease‐free survival was calculated for CR patients from the beginning of treatment until clinical or radiological and biopsy proven relapse." No information about patients who did not achieve CR. However, the denominator in the results section is the full population, not only patients in CR. Both disease‐free survival and relapse‐free survival were calculated but only disease‐free survival was reported. Due to the information given about toxic deaths, overall survival and disease‐free survival, we assumed that relapse‐free survival would also have been statistically significant and possibly similar to disease‐free survival, thus not resulting in any bias. In addition, disease‐free survival is preferable to relapse‐free survival as it includes deaths. For these reasons, we choose "unclear" and not "no". There is no information about progression‐free survival. No study protocol available.

Other bias

Unclear risk

Insufficient information to assess whether an important risk of bias exists.

Methods

Randomised controlled with two arms:

• Chemotherapy‐ alone arm and chemotherapy plus radiotherapy arm

Recruitment period:

• May 1990 to June 2000

• 152 patients randomised

• 152 patients evaluated for OS; 138 patients evaluated for response rate

• 14 patients not evaluated for response outcome

• 11 patients in the chemotherapy plus radiotherapy arm not receiving therapy as randomised

• Baseline patient's characteristics described

Median follow‐up time:

• 67 months (range 1 to 125 months)

ITT analysis for overall survival; no ITT analysis for response outcomes

Conducted by MSKCC (Memorial Sloan‐Kettering Cancer Center), USA

Participants

Inclusion criteria:

• Patients with a confirmed diagnosis of Hodgkin lymphoma, without previous treatment and with clinical or pathological stage IA, IIA, IIB or IIIA

• Lack of bulky nodal tumour (mediastinal mass ≤ 0.33, the thoracic diameter on chest x‐ray measured at T11, and/or peripheral or retroperitoneal adenopathy ≤ 10 cm in its largest diameter)

Exclusion criteria:

• Patients with chronic lung disease with a diffusing capacity of less than 60% and/or with cardiac disease with clinical congestive heart failure or an abnormal ventricular ejection fraction (< 50%) on echocardiogram or multiple gated acquisition scan

CS I, II:

• Chemotherapy alone: 19, 46

• Chemotherapy plus radiotherapy: 9, 58

CS III:

• Chemotherapy alone: 11

• Chemotherapy plus radiotherapy: 9

Prognostic features not reported

Median age:

• Chemotherapy alone: 33 years (range 16‐68 years)

• Chemotherapy plus radiotherapy: 39 years (range 15‐66 years)

Gender:

• 87 male, 65 female

• Small imbalance in the distribution of sex, stage and histology, regarding baseline patient's characteristics in comparison arms

• Histopathologic diagnosis: according to the Rye modification of the Lukes and Butler classification

Country:

• USA

Interventions

• Chemotherapy alone: 6 cycles of ABVD (doxorubicin (25 mg/m²), bleomycin (10 units/m²), vinblastine (6 mg/m²), dacarbazine (375 mg/m² intravenously, days1 and 15)); repeated after every 28 days

• Chemotherapy plus radiotherapy: same chemotherapy with extended‐field radiotherapy (EF‐radiotherapy) or involved‐field radiotherapy (IF‐radiotherapy); dose of radiotherapy 36 Gy in 180 cGy daily fractions starting after 4‐6 weeks after completion of chemotherapy

• Additional intervention: filgrastim was used for subsequent treatment of neutropenic patients

Outcomes

• Overall survival (reported, observation time 5 years)

• Complete response (reported)

• Partial response (reported)

• Time to progression reported (see Table 2)

Notes

• 13% patients with CS IIIA

• Academic funding

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequence generation was not reported. "Randomisation was performed after a check for eligibility. Patients were stratified according to clinical stage (IA or IIA, IIIA, I B or IIB)."

Presumably the randomisation was adequate.

Allocation concealment (selection bias)

Low risk

"Patients were enrolled by telephone call or fax to the MSKCC Clinical Trials Office".

Blinding (performance bias and detection bias)
Overall survival

Low risk

Patients and physicians not blinded. No information about blinding of the assessor. This is judged not to be a source of bias for overall survival.

Blinding (performance bias and detection bias)
Other outcomes

Unclear risk

Patients and physicians not blinded. No information about blinding of the assessor.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

OS: all patients included in the analysis, ITT‐analysis

Tumour control: all patients included in the analysis, ITT‐analysis

Response rates: 7/76 excluded from chemotherapy alone arm and 7/76 excluded from chemotherapy plus radiotherapy arm; three lost to follow‐up before completion of six cycles of chemotherapy and 11 stage IA patients with no measurable disease prior to treatment.

Selective reporting (reporting bias)

Unclear risk

Choice of progression outcome not described ‐ both disease‐free survival and freedom from progression evaluated; freedom from progression was closer to our definition of PFS and was thus used in the analyses. No study protocol available.

Other bias

High risk

11 patients randomised to radiotherapy never received radiotherapy:

6 refused, 4 progressed on chemotherapy prior to receiving radiotherapy, 1 never received radiotherapy because of bleomycin induced toxicity to radiotherapy.

Methods

Randomised controlled trial with two arms:

• Chemotherapy‐ alone arm and chemotherapy plus radiotherapy‐arm

Recruitment period:

• October 2003 to August 2010

• 602 patients enrolled

• 571 patients received PET‐scan

• 420 PET‐negative‐patients randomised:

  • 211 patients in chemotherapy‐ alone arm

  • 209 patients in chemotherapy plus radiotherapy arm

• Baseline patient characteristics described

Median follow‐up time:

• 60 months from randomisation

Information about not randomised patients provided

ITT analysis for OS and PFS

Participants

Inclusion criteria:

• Histologically confirmed diagnosis of Hodgkin lymphoma, without previous treatment and with clinical or pathological stage IA, IIA

• No stage IA Hodgkin lymphoma with no clinical or chemotherapy evidence of disease after diagnostic biopsy

• Above the diaphragm with no mediastinal bulk, defined as maximum transverse diameter of mediastinal mass, internal thoracic diameter at level of D5/6 interspace > 0.33

• Bulky disease at other sites, defined as nodal mass with transverse diameter ≥ 10 cm allowed

Exclusion criteria:

• Pregnant or nursing patients

• Fertile patients must use effective contraception during and for ≥ 6 months

• No prior malignancy except appropriately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix

• No severe underlying illness considered to make the trial therapy hazardous (i.e., severe heart disease or lung fibrosis)

• No contraindications to chemotherapy or radiotherapy

• Willing to travel to the nearest PET scan centre

• Able to comply with protocol follow‐up arrangement

420 patients randomised:

• Chemotherapy alone: 211

• Chemotherapy plus radiotherapy: 209

Patients not receiving therapy as randomised (28 of 420)

• Chemotherapy alone: 2 who received radiotherapy

• Chemotherapy plus radiotherapy: 26 who did not received radiotherapy (N = 19: patients or clinician choice, N = 5: death, N = 1: Pneumocystis jirovecii pneumonia, N = 1 withdrew consent)

Patients not randomised (182):

• Did not receive a PET scan: 31

• PET‐negative: 6

  • Patient choice: 3, clinician choice: 2, error: 1

• PET‐positive: 145

  • Patients received a fourth cycle of ABVD followed by IF‐radiotherapy

  • 126 are alive and progression free

  • 11 progressed

  • 8 died

Mean age of all 602 patients registered into the RAPID trial:

• 34 years (range 16 ‐ 75 years)

Gender of all 602 patients registered into the RAPID trial:

• 321 male, 281 female

Country:

• 94 Centres across UK

Interventions

Induction chemotherapy (all patients):

• All Patients received doxorubicin hydrochloride IV, bleomycin sulphate IV, vinblastine IV, and dacarbazine IV (ABVD) on days 1 and 15. Treatment repeats every 28 days for 3 courses

• On day 15 of the third course of chemotherapy, patients undergo a chemotherapy scan of the neck, thorax, abdomen and pelvis. Patients with non‐ responsive disease or progressive disease are removed from the study. Patients who achieve response undergo fludeoxyglucose F 18 positron emission tomography (FDG‐PET)

• Patients with reported ‘positive’ PET scan (score 3, 4 or 5 on a 5 point scale) had a 4th cycle ABVD and IF‐radiotherapy

• Patients with ‘negative’ PET scan (score 1 or 2) were randomised:

  • Chemotherapy alone: patients get no further treatment

  • Chemotherapy plus radiotherapy: patients get IF‐radiotherapy additional to the chemotherapy (30Gy delivered in daily fractions of 1.8 ‐ 2.0Gy)

• Dose not reported

Outcomes

• Progression­free survival (reported)

• Incidence of FDG ­PET scan positivity/negativity after 3 courses of chemotherapy (reported)

• Overall survival and cause of death (reported)

• Incidence and type of second cancers (not reported)

Notes

• Supported by Leukaemia and Lymphoma Research, the Lymphoma Research Trust, Teenage Cancer Trust, and the U.K. Department of Health

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information about the sequence generation progress. ("This is an ongoing randomized, controlled, non‐inferiority trial (...)").

Allocation concealment (selection bias)

Low risk

"Block randomization was performed at the Cancer Research UK and University College London Cancer Trials Centre; no stratification factors were used".

Blinding (performance bias and detection bias)
Overall survival

Low risk

Although the study is likely not to be blinded, this does not affect the outcome OS.

Blinding (performance bias and detection bias)
Other outcomes

Unclear risk

The study did not address blinding of participants or physicians. Regarding the study design it is likely that there was no blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All patients included in the analysis, ITT‐analysis

Selective reporting (reporting bias)

High risk

Study protocol available. Not all of the study’s pre‐specified secondary outcomes reported:

• Incidence and type of second cancers.

Other bias

High risk

28 of 420 patients did not received treatment as randomised: 2 received radiotherapy in chemotherapy alone arm and 26 did not received radiotherapy in the chemotherapy plus radiotherapy arm. These patients were still included in the analysis. In the chemotherapy plus radiotherapy arm 5 of the 8 deaths occurred in patients who received no radiotherapy.