Interventions for mycosis fungoides

Tobias Weberschock; Reinhard Strametz; Maria Lorenz; Christoph Röllig; Charles Bunch; Andrea Bauer; Jochen Schmitt

doi:10.1002/14651858.CD008946.pub2

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Figure 1

Study flow chart

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

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Figure 4

Forest plot of comparison: 5 IFN‐α + PUVA versus PUVA alone, outcome: 5.1 Clearance.

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Analysis 1.1

Comparison 1 Topical peldesine versus placebo, Outcome 1 Adverse effects.

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Analysis 1.2

Comparison 1 Topical peldesine versus placebo, Outcome 2 Clearance.

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Analysis 1.3

Comparison 1 Topical peldesine versus placebo, Outcome 3 Improvement.

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Analysis 2.1

Comparison 2 Topical imiquimod versus placebo, Outcome 1 Clearance.

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Analysis 2.2

Comparison 2 Topical imiquimod versus placebo, Outcome 2 Improvement.

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Analysis 3.1

Comparison 3 Topical hypericin versus placebo, Outcome 1 Improvement.

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Analysis 4.1

Comparison 4 IFN‐α versus placebo, Outcome 1 Adverse effects.

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Analysis 4.2

Comparison 4 IFN‐α versus placebo, Outcome 2 Clearance.

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Analysis 5.1

Comparison 5 IFN‐α + PUVA versus PUVA alone, Outcome 1 Clearance.

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Analysis 6.1

Comparison 6 Denileukin diftitox high versus low dose, Outcome 1 Adverse effects.

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Analysis 6.2

Comparison 6 Denileukin diftitox high versus low dose, Outcome 2 Clearance.

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Analysis 6.3

Comparison 6 Denileukin diftitox high versus low dose, Outcome 3 Improvement.

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Analysis 7.1

Comparison 7 Bexarotene high versus low dose, Outcome 1 Adverse effects.

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Analysis 7.2

Comparison 7 Bexarotene high versus low dose, Outcome 2 Clearance.

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Analysis 7.3

Comparison 7 Bexarotene high versus low dose, Outcome 3 Relapse.

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Analysis 7.4

Comparison 7 Bexarotene high versus low dose, Outcome 4 Improvement.

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Analysis 8.1

Comparison 8 Extracorporal photopheresis versus PUVA, Outcome 1 Clearance.

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Analysis 8.2

Comparison 8 Extracorporal photopheresis versus PUVA, Outcome 2 Improvement.

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Analysis 9.1

Comparison 9 Combined therapy versus conservative therapy, Outcome 1 Adverse effects.

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Analysis 9.2

Comparison 9 Combined therapy versus conservative therapy, Outcome 2 Clearance.

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Analysis 9.3

Comparison 9 Combined therapy versus conservative therapy, Outcome 3 Relapse.

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Analysis 9.4

Comparison 9 Combined therapy versus conservative therapy, Outcome 4 Survival rate.

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Analysis 9.5

Comparison 9 Combined therapy versus conservative therapy, Outcome 5 Improvement.

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Analysis 10.1

Comparison 10 IFN‐α + PUVA versus IFN‐α + acitretin, Outcome 1 Adverse effects.

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Analysis 10.2

Comparison 10 IFN‐α + PUVA versus IFN‐α + acitretin, Outcome 2 Clearance.

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Analysis 10.3

Comparison 10 IFN‐α + PUVA versus IFN‐α + acitretin, Outcome 3 Improvement.

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Analysis 11.1

Comparison 11 Topical nitrogen mustard with active transfer factor versus topical nitrogen mustard with inactivated transfer factor, Outcome 1 Clearance.

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Analysis 11.2

Comparison 11 Topical nitrogen mustard with active transfer factor versus topical nitrogen mustard with inactivated transfer factor, Outcome 2 Survival rate.

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Analysis 11.3

Comparison 11 Topical nitrogen mustard with active transfer factor versus topical nitrogen mustard with inactivated transfer factor, Outcome 3 Improvement.

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Table 1. Clinical staging system

2007 MF and Sézary syndrome		1979 CTCL		Disease‐specific survival rates in % (Agar 2010)
				5 year	10 year
IA	T1	IA	T1	98	95
	N0		N0
	M0		M0
	B0‐1		‐
IB	T2	IB	T2	89	77
	N0		N0
	M0		M0
	0‐1		‐
IIA	T1‐2	IIA	T1‐2	89	67
	N1‐2		N1
	M0		M0
	B0‐1		‐
IIB	T3	IIB	T3	56	42
	N0‐2		N0,1
	M0		M0
	B0‐1		‐
III	T4	III	T4
	N0‐2		N0,1
	M0		M0
	B0‐1		‐
IIIA	T4			54	45
	N0‐2
	M0
	B0
IIIB	T4			48	45
	N0‐2
	M0
	B1
IVA1	T1‐4	IVA	T1‐4	41	20
	N0‐2
	M0		N2‐3 ‐
	B2
IVA2	T1‐4		M0	23	20
	N3
	M0		‐
	B0‐2
IVB	T1‐4	IVB	T1‐4	18	not reached
	N0‐3		N0‐3
	M1		M1
	B0‐2		‐

Table 1. Clinical staging system

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Table 2. Glossary of terms

General medical terms	Explanation
Plaques	A solid elevated area on the skin that is more broad than it is high
Neoplasm	Any new and abnormal growth
Primary cutaneous lymphoma	Cutaneous T‐ and B‐cell lymphoma that primarily affect the skin
Cutaneous T‐cell lymphoma	Group of skin‐directed T‐cell neoplasms with diverse clinical and histological features and prognosis
Cutaneous B‐cell lymphoma	Group of skin‐directed B‐cell neoplasms with diverse clinical and histological features and prognosis
NK‐cell lymphoma	Group of neoplasms derived from the natural killer cells (NK‐cells) with diverse clinical and histological features and prognosis
Precursor haematologic neoplasm	Clinically‐aggressive neoplasm with a high incidence of cutaneous involvement and risk of leukaemic dissemination
Lesional skin atrophy	Death of the cells in the damaged area of skin
T‐cell	A type of lymphocyte (white cell)
Adverse effects

Acute myocardial infarction	Death of myocardial tissue due to blocked blood supply
Acute non‐lymphatic leukaemia	Serious disease with high production of non‐lymphatic leucocytes
ALT	The alanine transaminase is a liver enzyme (SGPT)
Anaemia	Low count of red blood cells
Anaemia hypochromic	Low count of red blood cells with low amount of haemoglobin, the red molecule that transports oxygen within the blood vessels
Anaphylactoid reactions	Very acute generalsied reaction with flush/urticaria, bad breathing, lowered blood pressure, nausea
Arthralgia	Joint pain
AST	The aspartate transaminase is an enzyme mainly present in the liver but also in the blood, muscle cells, and bones (SGOT)
Asthenia	Lack of energy or physical weakness or both
Cardiomyopathy	Structural or functional disease of the cardiac muscle
Cardiopulmonary syndrome	Adverse effect where the heart and the lung are involved
Chill	Shivering attack
CNS syndrome	Adverse effect where the central nervous system (brain, spinal cord) is involved
Cutaneous hypersensitivity	Altered reactivity to a specific antigen leading to cutaneous alterations
Cutaneous toxicity	Cutaneous adverse effect of an agent used in therapeutic dosages
Constipation	No stool
Dermatitis exfoliation	Inflammation and detachment of the skin
Diarrhoea	Many fluid stools
Dyspnea	Bad breathing
Erythema	Red dot or area on the skin
Fatigue	To be exhausted
Flu‐like symptoms	Symptoms which are often seen with influenza, such as fever, chills, and muscular pain
Gastrointestinal syndromes	Adverse effects affecting the digestive system (oesophagus, stomach, bowel)
Hair loss	Pathological increased loss of hair
Hepatotoxicity	Capacity of a substance to have damaging effects on the liver
Hospitalisation	Confinement of a patient in a hospital
Hypercholestaeremia	Elevated levels of cholesterol in the blood
Hyperlipaemia	Elevated levels of lipids in the blood
Hypotension	Low blood pressure
Hypothyroidism	Low function of thyroid gland
Impotentia	Inability to engage in sexual intercourse
Insomnia	Not being able to sleep
LDH	The lactate dehydrogenase is an enzyme which helps to produce energy in the body when oxygen is absent
Leukopenia	Low count of white blood cells
Malaise	To feel ill
Mucositis	Inflammation of mucosa
Myalgia	Muscle pain
Nasopharyngitis	Inflammation of the inner nose and the throat
nausea	About to vomit while feeling sick
Neuropathy	Abnormal state of the nervous system or nerves
Non‐melanoma skin cancer	Skin cancer which does not originate from melanocytes
Photosensitivity	Enhanced responsibility to light or ultraviolet light
Pruritus	Itching of the skin
Radiodermatitis	Dermatitis resulting from overexposure to sources of radiant energy
Rash	A lot of red dots on the skin
SGOT/SGPT	Liver enzymes, see also AST and ALT
T4	Enzyme of the thyroid gland
Thrombopenia	Low count of thrombocytes
Thrombotic syndrome	Blood coagulates within blood vessels
Triglycerid	Lipid
Vascular leak syndrome	When the blood vessels are not tight anymore and parts of the blood leak out in the surrounding tissue
Vasodilatation	Blood vessels widening

Table 2. Glossary of terms

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Table 3. List of abbreviations and acronyms

Acronym	Description (letters used for acronym in capitals)
ADF	Arbeitsgemeinschaft Dermatologische Forschung
BCNU	Carmustine, a nitrogen mustard related alkylating agent
CENTRAL	Cochrane Central Register of Controlled Trials
CI	Confidence interval
CTCL	Cutaneous T‐Cell Lymphoma
DDG	German Dermatologic Society
EORTC	European Organization of Research and Treatment of Cancer
ISCL	International Society for Cutaneous Lymphoma (ISCL)
ITT	Intention‐to‐treat
LILACS	Latin American and Caribbean Health Science Information database
MF	Mycosis Fungoides
PICOS	Participants, Interventions, Controls, Outcomes and Study
PRISMA	Preferred Reporting Items of Systematic Reviews and Meta‐Analyses
RCT	Randomised‐Controlled Trial
RR	Risk Ratio
TSEB	Total Skin Electron Beam
TNMB	Tumour, lymph Node, Metastasis and Blood
UK	United Kingdom
US	Unites States of America
USCLC	United States Cutaneous Lymphoma Consortium
WHO	World Health Organization

Table 3. List of abbreviations and acronyms

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Table 4. TNMB classifications

		2007 MF and Sézary syndrome	1979 CTCL
T: Skin
T0		N.E.	Clinically and/or histopathologically suspicious lesions
T1		Limited patches, papules, and/or plaques covering < 10% of the skin surface. May further stratify into T1a (patch only) versus T1b (plaque ± patch)	Limited plaques, papules, or eczematous patches covering < 10% of the skin surface
T2		Patches, papules, or plaques covering ≥ 10% of the skin surface. May further stratify into T2a (patch only) versus T2b (plaque ± patch)	Generalised plaques, papules, or erythematous patches covering ≥ 10% of the skin surface
T3		1 or more tumours ( ≥ 1 cm diameter)	Tumors, 1 or more
T4		Confluence of erythema covering ≥ 80% body surface area	Generalised erythroderma
N: Node
N0		No clinically abnormal peripheral lymph nodes; biopsy not required	No clinically abnormal peripheral lymph nodes palpable, histopathology negative for CTCL
N1		Clinically abnormal peripheral lymph nodes, histopathology Dutch grade 1 or NCI LN0‐2	Palpable Clinically abnormal peripheral lymph nodes, histopathology negative for CTCL
	N1a	Clone negative	‐
	N1b	Clone positive	‐
N2		Clinically abnormal peripheral lymph nodes, histopathology Dutch grade 2 or NCI LN3	No clinically abnormal peripheral lymph nodes, histopathology positive for CTCL
	N2a	Clone negative	‐
	N2b	Clone positive	‐
N3		Clinically abnormal peripheral lymph nodes, histopathology Dutch grades 3 to 4 or NCI LN4, clone positive or negative	Palpable clinically abnormal peripheral lymph nodes, pathology positive for CTCL
N3x		Clinically abnormal peripheral lymph nodes, no histologic confirmation	‐
M: Visceral
M0		No visceral organ involvement	No visceral organ involvement
M1		Visceral involvement (must have pathology confirmation and organ involved should be specified)	Visceral involvement (must have pathology confirmation and organ involved should be specified)
B: Blood
B0		Absence of significant blood involvement: Less than 5% of peripheral blood lymphocytes are atypical (Sézary) cells	Atypical circulating cells not present (less than 5%)
	B0a	Clone negative	‐
	B0b	Clone positive	‐
B1		Low blood tumour burden: More than 5% of peripheral blood lymphocytes are atypical (Sézary) cells but do not meet the criteria of B2	Atypical circulating cells present (more than 5%), record total white blood count and total lymphocyte counts, and number of atypical cells/100 lymphocytes
	B1a	Clone negative	‐
	B1b	Clone positive	‐
B2		High blood tumour burden: ≥ 1000/ µL Sézary cells with positive clone	‐
For the 'N' category histopathologic grading is necessary with the new 2007 TNMB classification. It may be either done via the Dutch System or the NCI/VA classification system (Sausville 1988; Scheffer 1980).

Table 4. TNMB classifications

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Table 5. Summary of effects of interventions

Study	Participants randomised	First intervention	Second intervention	Reported outcomes	baseline risk	Significant differences in outcome
Duvic 2001a	89 participants stage I (IA: 45, IB:44)	topical peldesine 1% given for 24 weeks	placebo cream given for 24 weeks	common adverse effects clearance survival rates improvement	common adverse effects (rash): 3% with placebo cream	common adverse effects (rash): The relative risk of 7.24 (95% CI 0.92 to 56.76) showed a higher risk for peldesine (Fisher test P≤0.041).
Chong 2004	4 participants plaque stage IB	topical imiquimod 5% given for 16 weeks	placebo cream given for 16 weeks	common adverse effects clearance (assessed 16 weeks after end of intervention) improvement (assessed 16 weeks after end of intervention) rare adverse effects		none
Rook 2010	12 participants patch or plaque stage, lesional comparison	hypericin 0.05‐0.25% in combination with visible light given for 6 weeks	placebo cream in combination with visible light given for 6 weeks	common adverse effects survival rates improvement	improvement: 8% with placebo cream	improvement: The relative risk of 7.00 (95% CI 1.01 to 48.54) favoured hypericin (Fisher test P≤0.028).
Vonderheid 1987	6 participants stage IA to IIA (IA: 1; IB: 1; IIA: 4), lesional comparison	injections of interferon‐α 2b given for 4 weeks	injections of isotonic sterile water given for 4 weeks	common adverse effects (assessed after 3 weeks of intervention) clearance (assessed 4 weeks after end of intervention)	common adverse effects (mild erythema): 0% with injections of sterile water clearance: 8% injections of sterile water	common adverse effects (mild erythema): The relative risk of 11.00 (95% CI 0.74 to 163.49) favoured interferon‐α (Fisher test P≤0.016). clearance: The RR 10.00 (95% CI 1.51 to 66.43) favoured interferon‐α (Fisher test P≤0.0007).
Wolff 1985	12 participants stage IA (7) to IB (5)	injections of interferon‐α given for 4 weeks	injections of buffered glycine serum human albumin given for 4 weeks	common adverse effects clearance	common adverse effects (mild fever): 0% with injections of buffered glycine serum human albumin	common adverse effects (mild fever): The relative risk of 11.00 (95% CI 0.70‐173.66) showed a higher risk for interferon‐α (Fisher test P≤0.03).
Stadler 2006	124 participants stage lA to IIA	injections of interferon‐α in combination with PUVA given for up to 52 weeks	PUVA alone given for up to 52 weeks	clearance		none
Wozniak 2008	29 participants stage lA to IIA (IA: 14; IB: 6; IIA: 9)	injections of interferon‐α in combination with PUVA given for 24 weeks	PUVA alone given for 24 weeks	clearance relapse disease‐free interval		none
Olsen 2001	71 participants stage IB‐IVA (IB:16, IIA: 10, IIB: 19, III: 11, IVA:15)	denileukin diftitox intravenous infusion 9µg/kg/day given for up to 6 months	denileukin diftitox intravenous infusion 18µg/kg/day given for up to 6 months	quality of life common adverse effects clearance survival rates (assessed 90 days after end of intervention) improvement rare adverse effects		none
Duvic 2001	58 participants stage I to IIA (IA: 17, IB: 34, IIA: 6, IIB: 1)	bexarotene capsules dosed 300 to 650mg/m²/day given for 16 weeks	bexarotene capsules dosed 6.5mg/m²/day given for 16 weeks	quality of life common adverse effects clearance relapse survival rates (assessed 4 weeks after end of intervention) improvement rare adverse effects		no calculations, due to methodological problems
Guitart 2002	43 participants stage IB (36) and IIA (7)	bexarotene 300mg/day in combination with PUVA and fenofibrate 54mg/day given for 24 weeks	bexarotene 150mg/day in combination with PUVA and fenofibrate 54mg/day given for 24 weeks	common adverse effects clearance relapse (assessed 6 months after end of intervention) disease‐free interval survival rates improvement	common adverse effects (cholesterol levels): 15% with bexarotene 150mg/day common adverse effects (triglyceride levels):25% with bexarotene 150mg/day	common adverse effects (cholesterol levels): The relative risk of 4.56 (5% CI 1.54 to 13.53) showed a higher risk for bexarotene 300mg/day (Fisher test P≤0.002). common adverse effects (triglyceride levels): The RR 3.16 (95% CI 1.93 to 6.98) showed a higher risk for bexarotene 300mg/day (Fisher test P≤0.002).
Child 2004	8 participants plaque stage (Bunn Lamberg 1B)	extracorporeal photopheresis given for 6 months	PUVA given for 3 months	common adverse effects clearance survival rates (assessed 2‐21 months after end of intervention) improvement	improvement:0% with extracorporeal photopheresis	improvement: The relative risk of 0.07 (95% CI 0.00 to 1.00) favoured PUVA (Fisher test P≤0.002).
Kaye 1989	103 participants of all stages (IA: 6, IB: 16, IIA: 9, IIB: 12; III: 2, IVA: 42, IVB: 16)	"combined therapy" (electron‐beam radiation and parenteral chemotherapy) given for 8 to 12 weeks	"conservative treatment" (topical treatment with mechlorethamine supported by a stepwise escalation of the therapy according to stage of disease) duration of intervention not reported	common adverse effects clearance relapse disease‐free interval survival rates (assessed more than 5 years after end of intervention) improvement	common adverse effects (hospitalisation): 0% with "conservative treatment" clearance: 18% with "conservative treatment" improvement: 65% with "conservative treatment"	common adverse effects (hospitalizations): The relative risk of 33.65 (95% CI 2.07 to 546.09) showed a higher risk for the "combined therapy" (Fisher test P≤0.0001). clearance: The relative risk of 2.18 (95% CI 1.10 to 4.33) favoured the "combined therapy" (Fisher test P≤0.03). improvement: The relative risk of 1.40 (95% CI 1.12 to 1.74) favoured the "combined therapy" (Fisher test P≤0.003).
Stadler 1998	82 participants stage I and II (IA: 36; IB: 28; IIA: 10; IIB: 8)	injections of interferon‐α in combination with PUVA given for up to 48 weeks	injections of interferon‐α in combination with acitretin given for up to 48 weeks	common adverse effects clearance improvement	common adverse effects (adverse effects grade III): 10% IFN‐α in combination with PUVA common adverse effects (requiring discontinuation): 5% IFN‐α in combination with PUVA common adverse effects (neurological disorders): 8% IFN‐α in combination with PUVA clearance: 38% with IFN‐α in combination with acitretin	common adverse effects (adverse effects grade III): The relative risk of 3.10 (95% CI 1.10 to 8.70) showed a higher risk for interferon‐α in combination with acitretin (Fisher test P≤0.03). common adverse effects (requiring discontinuation): The relative risk of 4.29 (95% CI 0.99 to 18.63) showed a higher risk for interferon‐α in combination with acitretin (Fisher test P≤0.049). common adverse effects (neurological disorders): The relative risk of 3.49 (95% CI 1.05 to 11.60) showed a higher risk for interferon‐α in combination with acitretin (Fisher test P≤0.04). clearance: The relative risk of 0.54 (95% CI 0.35 to 0.84) favoured interferon‐α in combination with PUVA (Fisher test P≤0.005).
Thestrup‐Pedersen 1982	16 participants van Scott stage II‐IV (II: 14; III: 1; IV: 1)	topically applied nitrogen mustard with active transfer factor given for 1 year	topically applied nitrogen mustard with inactivated transfer factor given for 1 year	common adverse effects clearance (assessed 1 year after end of intervention) survival rates (assessed 1 year after end of intervention) improvement (assessed 1 year after end of intervention)	clearance: 0% with topically applied nitrogen mustard with active transfer factor	clearance: The relative risk of 0.09 (95% CI 0.01 to 1.41) favoured topically applied nitrogen mustard with inactivated transfer factor (Fisher test P≤0.03).

Table 5. Summary of effects of interventions

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Table 6. Rare adverse effects detected by separate adverse event search

Intervention	Rare severe adverse effects
PUVA	transient lymphomatoid papulosis (Aronsson 1982) basal cell carcinoma/squamous cell carcinoma (Herrmann 1995) squamous cell carcinoma (Molin 1981) cataract (Rupoli 2005)
extracorporeal photopheresis	sarcoma (Korpusik 2008)
imiquimod	no reported SAEs found
electron beam	total epilation (Braverman 1987, Desai 1988), nail dystrophy/edema of hands and feet/bullae dorsum and feet/conjunctivitis/hospitalisation due to skin ulcers (Desai 1988) diffuse permanent telangiectasia/linear sclerosis/Ischaemic ulceration of finger tips (Micaily 1983)
cyclophosphamide, doxorubicin, etoposide, vincristine	haematologic toxicity: febrile neutropenia/staphylococcal bacteraemia/disseminated herpes infection/pneumocystis carinii pneumonia/neurologic toxicity grade 3/decreased left ventricular ejection fraction (Akpek 1999)
active transfer factor	no reported SAEs found
methotrexate	severe edematous erythroderma/denudation on the trunk and extremities/Interstitial pulmonary fibrosis (Zackheim 1996)
interferon‐alpha	acrocyanosis (Campo‐Voegeli 1998) oropharyngeal lichen planus (Kutting 1997) seizures (Legroux‐Crespel 2003) fatal neutropenia and sepsis (Vegna 1990) liver toxicity (Rupoli 2005, Simoni 1987, Vegna 1990)
bexarotene	neutropenia/non‐ST‐elevation myocardial infarction/elevated liver enzymes (Abbott 2009) lethal sepsis (Bohmeyer 2003)
peldesine (BCX‐34)	no reported SAEs found
denileukin diftitox (ONTAK)	lethal vascular leak syndrome with rhabdomyolysis (Avarbock 2008) grade 4 infusion event (Foss 2001)
nitrogen mustard	urticaria and anaphylactoid reaction (Daughters 1973, Grunnet 1976, Sanchez 1977) local bullous reaction (Goday 1990) perforating follicular mucinosis (Guilhou 1980) Stevens‐Johnson‐Syndrome (Newman 1997) cutaneous squamous/basal cell carcinoma (Hoppe 1987)

Table 6. Rare adverse effects detected by separate adverse event search

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Comparison 1. Topical peldesine versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Pruritus	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Rash	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Clearance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 Improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 1. Topical peldesine versus placebo

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Comparison 2. Topical imiquimod versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2 Improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 2. Topical imiquimod versus placebo

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Comparison 3. Topical hypericin versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 3. Topical hypericin versus placebo

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Comparison 4. IFN‐α versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse effects Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Erythema	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Fever	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Myalgia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Chills or weakness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.5 Nausea, arthralgia, and malaise	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Clearance Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 4. IFN‐α versus placebo

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Comparison 5. IFN‐α + PUVA versus PUVA alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	2	122	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.87, 1.31]

Comparison 5. IFN‐α + PUVA versus PUVA alone

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Comparison 6. Denileukin diftitox high versus low dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Constitutional symptoms	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Grade 3 to 4 constitutional symptoms	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Infections	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Grade 3 to 4 infections	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.5 Gastrointestinal syndromes	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.6 Grade 3 to 4 gastrointestinal syndromes	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.7 CNS syndromes	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.8 Grade 3 to 4 CNS syndromes	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.9 Rash	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.10 Grade 3 to 4 rash	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.11 Vascular leak syndrome	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.12 Grade 3 to 4 vascular leak syndrome	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.13 Thrombotic events	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.14 Grade 3 to 4 thrombotic events	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.15 Cardiopulmonary events	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.16 Grade 3 to 4 cardiopulmonary events	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.17 Acute infusion related events	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.18 Grade 3 to 4 acute infusion related events	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.19 Grade 3 to 4 laboratory abnormalities	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Clearance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 Improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 6. Denileukin diftitox high versus low dose

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Comparison 7. Bexarotene high versus low dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Photosensitivity	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Constipation	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Fatigue	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.5 Pruritus	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.6 Arthralgia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.7 Nasopharyngitis	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.8 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.9 Insomnia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.10 Free T4 abnormalities	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.11 Cholesterol abnormalities	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.12 Triglycerid abnormalities	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.13 SGOT/SGPT abnormalities	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Clearance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 Relapse Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4 Improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 7. Bexarotene high versus low dose

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Comparison 8. Extracorporal photopheresis versus PUVA

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2 Improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 8. Extracorporal photopheresis versus PUVA

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Comparison 9. Combined therapy versus conservative therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Hospitalization	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Fatal myocardial infarction	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Cutaneous toxicity from electron beam therapy	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Acute non‐lymphocytic leukaemia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.5 Non‐melanoma skin cancer	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.6 Unspecified	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Clearance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 Relapse Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4 Survival rate Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5 Improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 9. Combined therapy versus conservative therapy

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Comparison 10. IFN‐α + PUVA versus IFN‐α + acitretin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Grade I to II adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Grade III adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Adverse events requiring treatment discontinuation	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Flu‐like symptoms	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.5 Dryness/redness of skin or hair loss	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.6 Neurological disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.7 Psychiatric disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.8 Gastrointestinal disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.9 Elevated liver or biliary tract enzymes	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.10 Elevated triglycerides	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.11 Anemia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.12 Leukopenia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.13 Impotentia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.14 Redness and infiltration at application site	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Clearance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 Improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 10. IFN‐α + PUVA versus IFN‐α + acitretin

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Comparison 11. Topical nitrogen mustard with active transfer factor versus topical nitrogen mustard with inactivated transfer factor

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clearance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2 Survival rate Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 Improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 11. Topical nitrogen mustard with active transfer factor versus topical nitrogen mustard with inactivated transfer factor

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