Abstract

Background

Mycosis fungoides (MF) is the most common type of cutaneous T‐cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which may induce clinical remission for a time. This is an update of a Cochrane Review first published in 2012: we wanted to assess new trials, some of which investigated new interventions.

Objectives

To assess the effects of interventions for MF in all stages of the disease.

Search methods

We updated our searches of the following databases to May 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We searched 2 trials registries for additional references. For adverse event outcomes, we undertook separate searches in MEDLINE in April, July and November 2017.

Selection criteria

Randomised controlled trials (RCTs) of local or systemic interventions for MF in adults with any stage of the disease compared with either another local or systemic intervention or with placebo.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. The primary outcomes were improvement in health‐related quality of life as defined by participants, and common adverse effects of the treatments. Key secondary outcomes were complete response (CR), defined as complete disappearance of all clinical evidence of disease, and objective response rate (ORR), defined as proportion of patients with a partial or complete response. We used GRADE to assess the certainty of evidence and considered comparisons of psoralen plus ultraviolet A (PUVA) light treatment as most important because this is first‐line treatment for MF in most guidelines.

Main results

This review includes 20 RCTs (1369 participants) covering a wide range of interventions. The following were assessed as either treatments or comparators: imiquimod, peldesine, hypericin, mechlorethamine, nitrogen mustard and intralesional injections of interferon‐α (IFN‐α) (topical applications); PUVA, extracorporeal photopheresis (ECP: photochemotherapy), and visible light (light applications); acitretin, bexarotene, lenalidomide, methotrexate and vorinostat (oral agents); brentuximab vedotin; denileukin diftitox; mogamulizumab; chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine; a combination of chemotherapy with electron beam radiation; subcutaneous injection of IFN‐α; and intramuscular injections of active transfer factor (parenteral systemics).

Thirteen trials used an active comparator, five were placebo‐controlled, and two compared an active operator to observation only. In 14 trials, participants had MF in clinical stages IA to IIB. All participants were treated in secondary and tertiary care settings, mainly in Europe, North America or Australia. Trials recruited both men and women, with more male participants overall. Trial duration varied from four weeks to 12 months, with one longer‐term study lasting more than six years. We judged 16 trials as at high risk of bias in at least one domain, most commonly performance bias (blinding of participants and investigators), attrition bias and reporting bias.

None of our key comparisons measured quality of life, and the two studies that did presented no usable data. Eighteen studies reported common adverse effects of the treatments. Adverse effects ranged from mild symptoms to lethal complications depending upon the treatment type. More aggressive treatments like systemic chemotherapy generally resulted in more severe adverse effects.

In the included studies, CR rates ranged from 0% to 83% (median 31%), and ORR ranged from 0% to 88% (median 47%). Five trials assessed PUVA treatment, alone or combined, summarised below.

There may be little to no difference between intralesional IFN‐α and PUVA compared with PUVA alone for 24 to 52 weeks in CR (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.87 to 1.31; 2 trials; 122 participants; low‐certainty evidence). Common adverse events and ORR were not measured.

One small cross‐over trial found once‐monthly ECP for six months may be less effective than twice‐weekly PUVA for three months, reporting CR in two of eight participants and ORR in six of eight participants after PUVA, compared with no CR or ORR after ECP (very low‐certainty evidence). Some participants reported mild nausea after PUVA but no numerical data were given. One participant in the ECP group withdrew due to hypotension. However, we are unsure of the results due to very low‐certainty evidence.

One trial comparing bexarotene plus PUVA versus PUVA alone for up to 16 weeks reported one case of photosensitivity in the bexarotene plus PUVA group compared to none in the PUVA‐alone group (87 participants; low‐certainty evidence). There may be little to no difference between bexarotene plus PUVA and PUVA alone in CR (RR 1.41, 95% CI 0.71 to 2.80) and ORR (RR 0.94, 95% CI 0.61 to 1.44) (93 participants; low‐certainty evidence).

One trial comparing subcutaneous IFN‐α injections combined with either acitretin or PUVA for up to 48 weeks or until CR indicated there may be little to no difference in the common IFN‐α adverse effect of flu‐like symptoms (RR 1.32, 95% CI 0.92 to 1.88; 82 participants). There may be lower CR with IFN‐α and acitretin compared with IFN‐α and PUVA (RR 0.54, 95% CI 0.35 to 0.84; 82 participants) (both outcomes: low‐certainty evidence). This trial did not measure ORR.

One trial comparing PUVA maintenance treatment to no maintenance treatment, in participants who had already had CR, did report common adverse effects. However, the distribution was not evaluable. CR and OR were not assessable.

The range of treatment options meant that rare adverse effects consequently occurred in a variety of organs.

Authors' conclusions

​​There is a lack of high‐certainty evidence to support decision making in the treatment of MF. Because of substantial heterogeneity in design, missing data, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be reliably established on the basis of the included RCTs. PUVA is commonly recommended as first‐line treatment for MF, and we did not find evidence to challenge this recommendation. There was an absence of evidence to support the use of intralesional IFN‐α or bexarotene in people receiving PUVA and an absence of evidence to support the use of acitretin or ECP for treating MF.

Future trials should compare the safety and efficacy of treatments to PUVA, as the current standard of care, and should measure quality of life and common adverse effects.

Author(s)

Arash Valipour, Manuel Jäger, Peggy Wu, Jochen Schmitt, Charles Bunch, Tobias Weberschock

Abstract

Plain language summary

Treatments for mycosis fungoides (a malignant cancerous condition of immune cells in the blood that affects the skin)

What was the aim of this review?

This Cochrane Review compared treatments for mycosis fungoides (also called cutaneous T‐cell lymphoma, Alibert‐Bazin syndrome or granuloma fungoides).

What was studied in the review?

Mycosis fungoides (MF) typically starts as flat and scaly pink or red areas (patches) on the torso, upper thighs or buttocks. At this stage, life expectancy is unaffected. As the disease develops, life expectancy reduces. Patches can turn into raised, itchy plaques. Plaques can become thicker, deeper, and develop into tumours. In rare cases, the disease spreads to other organs.

Many treatments exist for MF; these target specific body areas (local therapy) or the entire body (systemic therapy). Treatments include creams, ointments, oral or injected medicines, light therapy, radiotherapy (radiation that kills cancer cells) and chemotherapy (medicines that kill cancer cells).

We compared the benefits and harms of different treatments in adults, at different disease stages. We identified 20 studies published up to May 2019.

The studies included 1369, mainly male, adults. Most ran from 4 weeks to 12 months. Only five studies investigated the later stages of disease. All were set in specialised healthcare centres in Europe (12 studies), North America (11 studies), Australia (three studies), Brazil and Japan (one study each; satellite centres for studies already listed). Treatments were compared with another treatment (13 studies); an inactive treatment (placebo) (five studies); or no treatment (two studies).

Five studies did not report their funding. Eleven studies were funded by pharmaceutical companies and four by academic institutions or hospitals.

Key results

We do not know how different treatments for MF affect quality of life. Very few studies assessed this outcome and they presented no usable data.

Unwanted (adverse) effects ranged from mild symptoms to severe life‐threatening complications. More aggressive treatments (such as chemotherapy) generally caused more severe adverse effects.

PUVA (a light treatment) is the first treatment used for MF. Results from five studies provided low‐certainty evidence:

There may be little to no difference between giving PUVA alone and PUVA plus injected interferon‐α (IFN‐ α) (a messenger substance of the immune system) for 24 to 52 weeks for making the disease disappear completely. No studies investigated adverse events in these treatments or disappearance of at least 50% of the disease.

There may be little to no difference between an oral vitamin A derivative (bexarotene) plus PUVA, and PUVA alone, for complete or at least 50% disease disappearance (treatment duration: up to 16 weeks). Extreme sensitivity to ultraviolet (UV) rays occurred in some people who received bexarotene and PUVA, but not PUVA alone.

There may be little to no difference between IFN‐ α plus PUVA and IFN‐α plus acitretin (another oral vitamin A derivative) on flu‐like symptoms, when treatment is given for up to 48 weeks or until complete disease disappearance. However, there may be a lower rate of complete disease disappearance with IFN‐α plus acitretin. No studies investigated the effect on partial disappearance.

It is not clear how PUVA maintenance treatment (to prevent the disease from reappearing after it has disappeared) compares with no maintenance treatment, since the only study on this reported very limited information.

One small trial (eight people) compared extracorporeal photopheresis (ECP, a light therapy) once monthly for six months with twice‐weekly PUVA for three months. It reported complete or at least 50% disappearance of MF in some participants treated with PUVA and none who received ECP. Common side effects were reported with each treatment (PUVA may be associated with mild nausea, and ECP with hypotension). However, the very‐low certainty evidence means we are not sure of these results.

How confident are we in the results of this review?

Our confidence in the results of this review is mainly low, but very low for one set of key results. The review is based on small and poorly designed studies. Further research is likely to change its message.

Conclusion

We found no evidence to challenge or support the standard treatment (PUVA). In the absence of a cure, treatment of MF should be based on disease stage, with a focus on limiting severe adverse effects.

Author(s)

Arash Valipour, Manuel Jäger, Peggy Wu, Jochen Schmitt, Charles Bunch, Tobias Weberschock

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

At this point, no exact cause for the disease has been found and no curative treatment for mycosis fungoides (MF) has been established.

Our review found the following key findings.

• There may be little to no difference between psoralen plus ultraviolet A (PUVA) alone versus PUVA plus interferon‐α (IFN‐α) in complete response (low‐certainty evidence). This comparison did not report the objective response rate (ORR).
• Very low‐certainty evidence means that we are uncertain of the effects of extracorporeal photopheresis (ECP) compared with PUVA on the reported outcomes of complete response (CR) and ORR with PUVA.
• There may be little to no difference in CR and ORR in participants given bexarotene in combination with PUVA compared to PUVA alone (low‐certainty‐evidence).
• Low‐certainty evidence indicates that IFN‐α + acitretin may lead to a lower complete response rate than IFN‐α + PUVA. This comparison did not report the ORR.
• One study compared PUVA maintenance versus no maintenance in patients with CR, but our key outcomes were not assessable or data were not provided.
• Mild nausea was reported by some participants after PUVA, and one participant withdrew from the ECP group due to hypotension (very‐low certainty evidence). In the bexarotene plus PUVA group, one participant reported photosensitivity compared to no participants in the PUVA‐alone group (low‐certainty evidence). There may be little to no difference between IFN‐α combined with either PUVA or acitretin in the occurrence of flu‐like symptoms (low‐certainty evidence). Common adverse events were not measured in the comparison of PUVA alone versus PUVA plus IFN‐α (low‐certainty evidence).

The interventions in our review showed a wide range of adverse effects, some of them potentially life‐threatening. Generally, the studies suggested that more aggressive therapeutic approaches led to substantially increased, and more severe, adverse effects.

When treating MF, the clinician should be aware of the limited evidence supporting the different types of treatments. Despite a wide variety of existing treatments for MF, the data we extracted from the 20 randomised controlled trials (RCTs) in this systematic review did not provide us with much useful evidence. The studies included only, on average, 68 participants and showed heterogeneous designs, making it difficult to draw firm conclusions. Only five trials assessed PUVA treatment, either given alone or combined.

In the early stages of this disease, skin‐directed treatment approaches are more often recommended than systemic or combination therapies because progression of the disease is slow, and in the very early stages life expectancy is similar to age‐matched control groups. In this review, we were not able to include RCTs investigating the effect of topical corticosteroids versus placebo. Despite its widespread use, no RCTs could be included in this review investigating the effect of UVB or localised radiotherapy.

Even if the majority of the reviewed trials compared an intervention to an active comparator, clinicians and people with early stage MF should consider what is called 'watchful waiting' or 'expectant policy' as one of their treatment options. Treating patients at early stages of disease might temporary improve their condition. Nevertheless, potential adverse effects can negatively affect quality of life resulting in lower therapeutic value.

Clinicians should motivate people with MF to enter multicentre RCTs, especially for advanced stages of MF as they represent an unmet medical need, in order to facilitate evidence‐based recommendations.

Implications for research 

Research should be based on commonly‐accepted diagnostic and staging criteria. With the publication of the joint consensus statement of the ISCL, EORTC and the United States Cutaneous Lymphoma Consortium (USCLC) by Olsen 2011, commonly‐accepted criteria have been established regarding the conduct of MF studies and their outcome measurements. The consensus statement emphasised the RCT as the ideal and a goal that may be reached by co‐operative studies.

For all studies, the stage of the disease and its activity are needed in order to refer treatments under investigation to a suitable group of participants. The inclusion of subtypes of MF should be clearly stated, and it is recommended that the results are stratified according to the different MF entities. A joint commitment of the specialised centres to high‐quality multicentre RCTs would be helpful to gain sufficient sample sizes.

Regarding the two primary outcome measures chosen for this review, it is surprising that while quality of life measurements are paid attention to in an extra chapter in the consensus statement, no end points were proposed on how to measure or address adverse effects. This might be due to the fact that many clinicians do not consider adverse effects to be a relevant end point for studies at all, but still we remain of the opinion that they should be reported in all further trials regarding the treatment of MF.

The first‐line treatment options already recommended for early stages (i.e. topical application of corticosteroids, nitrogen mustard, hypericin, intralesional injection of IFN‐α, or PUVA) should be a primary target for further research, since they apply to the largest group of people with MF. Treatment options often used as concomitant therapy, such as topical corticosteroids, should be investigated for their inherent efficacy.

Comparable, clearly‐defined, and standardised end points have been proposed by international societies, and they should be consistently used in further research in order to gain comparability (Olsen 2011). Furthermore, involvement of patients at the stage of study design would lead to adequate evaluations of their desires and needs. In addition to efficacy measures, toxicities should be reported not only by physicians but also by patients in order to facilitate the decision for treatment allocation. Quality of life should be addressed based on different treatment arms and not according to response as has been done in the included studies. A measure of the quality of life was often not implemented in the RCTs under investigation, but is essential in order to balance the risks and benefits of treatments. This is particularly applicable to early stage disease where life expectancy is not likely to be affected.

Validated patient‐reported outcome measures are crucial for the comparison of different interventions.

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