Cancer Management and Research Dovepress

open access to scientific and medical research

Open Access Full Text Article REVIEW

Management of mycosis fungoides-type

cutaneous T-cell lymphoma (MF-CTCL): focus on
chlormethine gel
This article was published in the following Dove Medical Press journal:
Cancer Management and Research downloaded from https://www.dovepress.com/

Cancer Management and Research

Daphné Denis 1 Abstract: Mycosis fungoides (MF) is a low-grade cutaneous lymphoma accounting for more
Nathalie Beneton 1 than half of primary cutaneous T-cell lymphomas (CTCLs). Due to the rarity of CTCL, random-
Kamel Laribi 2 ized studies are lacking, and treatment is based mainly on the recent published European Organ-
Hervé Maillard 1 isation for Research and Treatment of Cancer guidelines. Basically, early-stage MF is treated
For personal use only.

with skin-directed treatments, whereas advanced-stage MF requires more aggressive therapies.

1
Dermatology Department, Centre
Hospitalier Le Mans, Le Mans, France; Among the skin-directed therapies, nitrogen mustard has been used for more than 50 years. A
2
Haematology Department, Centre gel formulation was developed recently, showing a slight decrease in efficacy, counterbalanced
Hospitalier Le Mans, Le Mans, France by better tolerance (essentially due to a decrease in delayed hypersensitivity reactions). This
review aims to summarize the current management of MF and the role of chlormethine gel in
the treatment of the disease.
Keywords: mycosis fungoides, nitrogen mustard, mechlorethamine, chlormethine, gel
Video abstract
Introduction
Cutaneous T-cell lymphomas (CTCLs) are a group of extranodal non-Hodgkin lym-
phomas that account approximately for 2% of all lymphomas.1 Classification follows
the 2016 revision of the World Health Organization (WHO) classification of cutaneous
lymphomas.2 Mycosis fungoides (MF) is a low-grade cutaneous lymphoma account-
ing for more than half of all primary cutaneous lymphomas.1 Sézary syndrome (SS)
is rarer, accounting for around 5% of cases.

Histology
Point your SmartPhone at the code above. If you have a MF is defined histologically by an initial skin infiltration with atypical cells having
QR code reader the video abstract will appear. Or use:
http://youtu.be/p9dj5TUlRA0 cerebriform nuclei, often located in the basal layer of the epidermis, which is called epi-
dermotropism. These cells are clonally derived malignant CD4+CD45RO+-phenotype
T lymphocytes lacking normal T-cell markers, such as CD7 and CD26.3 The diagnosis
is often made after several aspecific biopsies.

Correspondence: Daphné Denis

Dermatology Department, Centre Epidemiology
Hospitalier Le Mans, 194 Avenue MF typically affects old adults with median age at diagnosis of 55–60 years, with a
Rubillard, Le Mans 72037, France
Tel +33 24 471 0774
male-to-female ratio of 1.6–2:1.4 Incidence has been stable since 1995, at around 5.6
Email [email protected] per million persons.5 It may also occur very rarely in children and adolescents.6

submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11 2241–2251 2241
Dovepress © 2019 Denis et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.
http://dx.doi.org/10.2147/CMAR.S138661
php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work
you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For
permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
Denis et al Dovepress

Clinical presentation
The clinical presentation of MF varies from patches or
plaques in the early stages, often situated in sun-protected
areas, to cutaneous tumors, sometimes with lymph node,
visceral, or blood involvement4 (Figures 1 and 2). Some
clinical variants, such as folliculotropic MF, pagetoid
reticulosis, and granulomatous slack skin, were sepa-
rated in the WHO–European Organization for Research
and ­Treatment of Cancer (EORTC) classification,1,2 due
to d­ ifferent c­ linicopathological features and biological
response.

Two different diseases

Most of the time, MF is an indolent disease, and the prog-
nosis of patients with MF is extremely dependent on the
tumor-node-metastasis-blood (TNMB) stage at diagnosis4,7
(Table 1). Recent guidelines have been published in 2017
by the EORTC.5 Figure 2 Mycosis fungoides “plaques” stage
In early-stage MF (IA–IIA), representing around 70%
of patients, most patients can look forward to a normal life
expectancy and the treatment aim is to prevent evolution to
Sézary syndrome
SS is by definition an advanced disease, pathologically and
a more severe disease. Recommendations in theses stages
clinically related to MF. It mostly presents with erythema,
are to use skin-directed treatments. Recently, a difference in
together with lymphadenopathy and blood involvement with
prognosis has been highlighted between patches and plaques
Sézary cells. The prognosis is poor, with median survival of
(T1/2a/b), with a poorer prognostic in the plaque diseases.
<3 years.8
(T1b or T2b).7 On the contrary, patients with advanced
disease have a severe prognosis and have to be treated with
chemotherapy, which often fails to offer durable remission,
Management of mycosis fungoides
except for the highly selected subset of patients eligible for Staging
allogeneic stem-cell transplantation. New therapeutics are As a first step, patients have to be investigated with a clinical
emerging, and clinical trials have to be proposed to patients and histological confrontation. Blood and sometimes blood-
if available. marrow investigations, as well as radiological tests, are to be
staged following EORTC directives. Treatment will depend on
the patient’s comorbidities and severity of disease based on this
staging. For patients with clinical stage IA–IB and no palpable
lymphadenopathy, no extensive staging evaluation is recom-
mended. Suspicious lymph nodes, ie, >1.5 cm in diameter
and/or firm, irregular, or clustered, have to be biopsied (core
or excisional biopsy) for light-microscopy pathologic assess-
ment, flow cytometry, and T-cell-receptor gene rearrangement.
Chest, abdomen, and pelvis computed tomography should
be performed in patients with anything other than IA disease
or with limited IB disease. In cases of potential lymphade-
nopathy, visceral involvement, or abnormal laboratory tests,
fludeoxyglucose positron-emission tomography could be
performed as well for further investigations. Bone-marrow
biopsy is usually not required, unless there are unexplained
hematologic abnormalities. These recommendations are
Figure 1 Mycosis fungoides “patches” stage. outlined in Table 3.

2242 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11
Dovepress
 Dovepress Denis et al

Table 1 ISCL/EORTC revision of the classification of mycosis fungoides and Sézary syndrome
Skin
T1 Limited patches,a papules, and/or plaquesb covering <10% of skin surface
T1a patch only
T1b patch ± plaque
T2 Patches, papules, and/or plaques covering >10% of skin surface
T1a patch only
T1b patch ± plaque
T3 One or more tumors (>1 cm diameter)c
T4 Confluence of erythema covering >80% of body-surface area
Node
N0 No clinically abnormal peripheral lymph nodesd (biopsy not required)
N1 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0–2
N1a Clone-negativee
N1b Clone-positivee
N2 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3
N2a Clone-negativee
N2b Clone-positivee
N3 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 3–4 or NCI LN4
Nx Clinically abnormal peripheral lymph nodes; no histological confirmation
Visceral
M0 No visceral organ involvement
M1 Visceral involvement (must have pathology confirmationf, and organ involved should be specified)
Blood
B0 Absence of significant blood involvement <5% of peripheral blood lymphocytes are atypical (Sézary) cellsg
B0a Clone-negativee
B0b Clone-positivee
B1 Low blood-tumor burden: >5% of peripheral blood lymphocytes are atypical (Sézary) cells, but does not meet the criteria of B2
B1a Clone-negativee
B1b Clone-positivee
B2 High blood-tumor burden: >1,000 µg/L Sézary cells with positive clone
Notes: aFor skin, “patch” indicates any size skin lesion without significant induration or elevation. Presence or absence of hypo- or hyperpigmentation, scale, crusting, and/or
poikiloderma should be noted. bFor skin, “plaque” indicates any skin lesion that is elevated or indurated. Presence or absence of hypo- or hyperpigmentation, scale, crusting,
and/or poikiloderma should be noted. Histological features, such as folliculotropism or large-cell transformation (>25% large cells), CD30+ or CD30–, and clinical features,
such as ulceration, are important to document. cFor skin, “tumor” indicates at least 1 cm-diameter solid or nodular lesion with evidence of depth and/or vertical growth.
Note total number of lesions, total volume of lesions, largest lesion, and region of body involved. Also note if histological evidence of large-cell transformation has occurred.
Phenotyping for CD30 is encouraged. dFor nodes, abnormal peripheral lymph node(s) indicates any palpable lymph node that on physical examination is firm, irregular,
clustered, fixed, or ≥1.5 cm in diameter. Central nodes, which are generally amenable to pathological assessment, are not currently considered in nodal classification, unless
to establish N3 histopathologically. eA T-cell clone is defined by PCR or Southern blot analysis of the T-cell-receptor gene. fFor viscera, spleen and liver may be diagnosed
by imaging criteria. gFor blood, Sézary cells are defined as lymphocytes with hyperconvoluted cerebriform nuclei. If Sézary cells are not able to be used to determine tumor
burden for B2, than one of the following modified ISCL criteria with positive clonal rearrangement of the T-cell receptor may be used instead: expanded CD4+ or CD3+ cells
with CD4:CD8 ratio ≥10, and expended CD4+ cells with abnormal immunophenotype, including loss of CD7 or CD26. Republished with permission of American Society of
Hematology, from Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas
(ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC), Olsen E, et al, 110, 6, 2007; permission
conveyed through Copyright Clearance Center, Inc.
Abbreviations: ISCL, International Society for Cutaneous Lymphomas; EORTC, European Organization for Research and Treatment of Cancer; NCI, National Cancer
Institute.

Treatment recommendations by disease important to note that there is currently no curative treatment
stage for MF (except for allogeneic stem-cell transplantation). The
In view of the rarity of CTCL, randomized clinical studies are main treatment objective is to reach effective palliation with
lacking, and treatment is based mainly on the recently pub- symptom improvement and/or enhance the patient’s quality
lished EORTC guidelines.5 This lack of evidence-based data of life.5 The risk of infection in patients undergoing immu-
leads to heterogeneity of treatment approaches, especially nosuppressive treatment is important, and patients should be
between US and non-US centers and between institutes.8 It is carefully monitored.

Cancer Management and Research 2019:11 submit your manuscript | www.dovepress.com

2243
Dovepress

Powered by TCPDF (www.tcpdf.org)

 Denis et al Dovepress

Table 2 ISCL/EORTC revision of mycosis fungoides and Sézary Early-stage MF: IA–IIA
syndrome staging4
Frontline treatment
T N M B Frontline treatments for early stages are dominated by skin-
IA 1 0 0 0, 1
directed therapies.
IB 2 0 0 0, 1
IIA 1, 2 1, 2 0 0, 1
IIBa 3 0–2 0 0, 1 Topical corticosteroids
IIIa 4 0–2 0 0, 1 Only one controlled study has evaluated this treatment,9 with
IIIAa 4 0–2 0 0 high potency compared to less potent topical steroids;5 how-
IIIBa 4 0–2 0 1
IVA1a 1–4 0–2 0 2
ever it is widely used. Clobetasol propionate is used mainly.
IVA2a 1–4 3 0 0–2 It is a simple treatment for patients with a low number of
IVBa 1–4 0–3 1 0–2 patches or plaques.
Note: aConsidered advanced-stage disease. Republished with permission of
American Society of Hematology, from Revisions to the staging and classification
of mycosis fungoides and Sezary syndrome: a proposal of the International Society Topical mechlorethamine
for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the
European Organization of Research and Treatment of Cancer (EORTC), Olsen E, Mechlorethamine or nitrogen mustard (NM) has been used
et al, 110, 6, 2007; permission conveyed through Copyright Clearance Center, Inc. in MF in the US since 1949.5 This topical chemotherapy
Abbreviations: ISCL, International Society for Cutaneous Lymphomas; EORTC,
European Organization for Research and Treatment of Cancer; works as an alkylating agent by affecting rapidly dividing

Table 3 Recommended evaluation/initial staging of patients with mycosis fungoides/Sézary syndrome4

Complete physical examination, including:
• determination of type of skin lesion(s)
• if only patch/plaque disease or erythema: estimate percentage of body surface involved and note any ulceration of lesions
• if tumors are present: total number of lesions, aggregate volume, largest lesion, and region of body involved
• identification of any palpable lymph node, especially those ≥1.5 cm in largest diameter or firm, irregular, clustered, or fixed
• identification of any organomegaly
Skin biopsy
• Most indurated area if only one biopsy
• Immunophenotyping to include at least CD2, CD3, CD4, CD5, CD7, CD8, and a B-cell marker, such as CD20 or CD30, may also be indicated in
cases where lymphomatoid papulosis, anaplastic lymphoma or large-cell transformation is considered
• Evaluation for clonality of TCR gene rearrangement
Blood tests
• Complete blood count with manual differential, liver-function tests, LDH, comprehensive chemistry
• TCR gene rearrangement and relatedness to any clone in skin
• Analysis for abnormal lymphocytes by either Sézary cell count with determination of absolute number of Sézary cells and/or flow cytometry
(including CD4+/CD7– or CD4+/CD26–)
Radiological tests
• In patients with T1N0B0-stage disease who are otherwise healthy and without complaints directed to a specific organ system and in selected
patients with T2N0B0 disease with limited skin involvement, radiological studies may be limited to a chest X-ray or ultrasound of the peripheral
nodal groups to corroborate absence of adenopathy
• In all patients with other than presumed stage IA disease, or selected patients with limited T2 disease and the absence of adenopathy or blood
involvement, computed tomography of chest abdomen and pelvis ± fludeoxyglucose positron-emission tomography are recommended to
further evaluate any potential lymphadenopathy, visceral involvement, or abnormal laboratory tests. In patients unable to undergo computed
tomography safely, magnetic resonance imaging may be substituted.
Lymph-node biopsy
• Excisional biopsy is indicated in those patients with a node that is either ≥1.5 cm in diameter and/or is firm, irregular, clustered, or fixed.
• Site of biopsy
• Preference is given to the largest lymph node draining an involved area of the skin, or if fludeoxyglucose positron-emission-tomography data are
available, the node with highest standardized uptake value.
• If there is no additional imaging information and multiple nodes are enlarged and otherwise equal in size and consistency, the order of preference
is cervical, axillary, and inguinal areas.
• Analysis: pathologic assessment by light microscopy, flow cytometry, and PCR gene rearrangement
Note: Republished with permission of American Society of Hematology, from Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a
proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of
Cancer (EORTC), Olsen E, et al, 110, 6, 2007; permission conveyed through Copyright Clearance Center, Inc.
Abbreviation: TCR, T-cell receptor.

2244 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11
Dovepress

Powered by TCPDF (www.tcpdf.org)

 Dovepress Denis et al

cells through DNA cross-linking, abnormal base pairing, or Retinoids (including bexarotene)
nucleic acid depurination. It may also alter the tumor-growth Among these molecules, bexarotene is the only one that was
pattern and enhance immunogenic host potential.10 It was developed and approved specifically for the treatment of
initially prepared in water, then in ointment form, and later CTCL. It is indicated in patients with MF refractory to at least
a gel formulation was introduced. one prior therapy.23 The overall response rate is 31%–51%,
depending on the study end-point definition.23 Acitretin and
Topical bexarotene isotretinoin are also commonly used.24 The main adverse events
A 1% gel formulation was approved as a second-line treat- (AEs) behind the teratogenic effect are drying of the skin and
ment by the US Food and Drug Administration (FDA), mucosa, hyperlipidemia, and central hypothyroidism.24
based on a prospective phase III study reporting an overall
response rate of 46%.13 In Europe, some practitioners use this Interferon-α
treatment off-label in patients who have not tolerated other Recombinant IFNα is the most widely used drug, but with
local therapies, as the toxicity is mild. Like every retinoid, varying treatment schedules. EORTC guidelines recommend
bexarotene is teratogenic. starting with 3 million units three times a week. The overall
response rate ranges from 0 to 80%.25 Given its inhibitory
Ultraviolet phototherapy effects on eosinophil chemotaxis and activation,8 it is very
Psoralen plus ultraviolet A (PUVA), as well as UVB are both useful in patients with eosinophilia.
recommended in MF. A recent review highlighted the lack of
evidence in terms of long-term efficacy and safety, because Low-dose methotrexate
of the lack of standardization between studies. It aimed at This cytotoxic treatment is commonly used alone26 or in
providing guidelines for clinicians and investigators.14 This association with IFN27 in refractory MF. The recommended
treatment offers the advantage of rapid relief in pruritus and dose is 10–25 mg once weekly.5
lesion size. The main limitations are accessibility of the treat-
ment and the potential risk of secondary skin cancer. This Combinations of these treatments
was studied in psoriasis, but not in MF,15,16 and proven only Combinations, mostly of PUVA with retinoids, or less clas-
with PUVA. This treatment has also been reported as a safe sically with IFNα, and of retinoids (acitretin) and IFNα, are
and effective option in childhood MF.17 used.28 Methotrexate (Mtx) has also been combined with
IFNα, phototherapy, and radiotherapy.29 These systemic ther-
Localized radiotherapy apies are also often combined with skin-directed therapies.5
Especially indicated in individual or localized lesions, alone
or in combination with other therapies, radiotherapy may Advanced-stage MF
even induce long-term remission. The treatment can also be In addition to the EORTC guidelines, a recent retrospective
effective in pagetoid reticulosis.18 study from the Cutaneous Lymphoma International Consor-
tium reported the most common approaches by stage,30 and a
Photodynamic therapy with methylaminolevulinic acid recent review also focused on this advanced-stage disease.8
A recent prospective French study evaluated this treatment
in 20 patients with paucilesional forms, and reported an First-line treatment
ORR of 75%, with good tolerance.19 A recent Italian review Stage IIB: patients with cutaneous tumors
confirmed this effectiveness.20 When patients show MF with tumors, the same systemic
treatments as in second-line treatment of early-stage MF are
Second-line treatment recommended,5 with bexarotene being the most commonly
In second-line treatment, systemic therapies are most com- used,30 followed by localized radiotherapy, total-skin electron-
monly used. beam therapy, and gemcitabine.5 Low-dose Mtx, IFNα, and
PEGylated liposomal doxorubicin can also be used.
Total-skin electron-beam therapy
In this therapy, a linear accelerator generates attenuated Stage III: patients with erythematous MF or SS
electrons that penetrate the skin to a limited depth, thus In stage IIIA, Mtx is the most commonly used treatment.
avoiding internal organ toxicity. There is a debate between The dose in this regimen is often 25 mg weekly.31 In stage
conventional doses or low-dose therapy.21,22 IIIB, the same treatments are recommended, alone or in

Cancer Management and Research 2019:11 submit your manuscript | www.dovepress.com

2245
Dovepress

Powered by TCPDF (www.tcpdf.org)

 Denis et al Dovepress

combination with extracorporeal photochemotherapy,5 where IgG1 antibody attached to a microtubule-disrupting agent,
blood is exposed to photoactivated 8-methoxypsoralen.32 This which after internalization induces cell-cycle arrest. The
treatment is well tolerated and efficient. The main difficulty main limiting AE is neurosensitive peripheral neuropathy.
is accessibility. It is often associated with IFN, bexarotene, • Mogamulizumab is a humanized monoclonal antibody
retinoids. The reported response rate is 20%–63%.8 that targets the CC chemokine receptor 4, modified by
glycoengineering to enhance its antibody-dependent
Stage IV: patients with high-grade lymph-node involvement cell-mediated cytotoxicity. It recently showed significant
and/or blood involvement with or without SS improvement in ORR and progression-free survival over
Patients are treated with radiotherapy and/or chemotherapy, vorinostat in 372 patients with advanced-stage MF as
except for highly selected patients who can undergo allogeneic second-line treatment in the MAVORIC study,39 with
stem-cell transplantation. This is the only curative treatment for median progression-free survival of 7.7 vs 3.1 months and
MF. Patient selection must be very careful, given the high mor- improved ORR of 28% vs 4.4%. It is especially interest-
bidity rate of this treatment (immunomediated graft-versus-host ing in patients with blood involvement. This treatment is
disease effect).33 In stage IVA, photopheresis is the most com- approved in Japan and in the US, but not available yet in
mon first-line treatment, followed by IFNα and chlorambucil.30 Europe. AEs include flu-like symptoms, rash (two cases
In aggressive forms with blood involvement (IVB), poly- of Stevens–Johnson syndrome), and infusion reactions.8
chemotherapy is used as first-line treatment, with the cyclo- • Alemtuzumab is an anti-CD52 human IgG-derived mono-
phosphamide–hydroxydaunorubicin–oncovin–prednisolone clonal antibody. Although it is commercialized to treat
regimen being most widely used, but other combinations multiple sclerosis, it is available through a special-access
are available.5 In SS, chlorambucil–prednisone is used. It is program for the treatment of lymphoid neoplasms. A
worthy of mention that there are specific recommendations phase II study showed an overall response rate of 55%,40
for SS published by the United States Cutaneous Lymphoma with a preferential use in erythematous MF/SS. A recent
Consortium that insist on several principles, such as preserv- study has shown long-term remission in this subgroup
ing host immunity by using immunomodulatory therapy of patients.41 The main AEs are opportunistic infections,
before chemotherapy, unless burden of disease or failure of including cytomegalovirus replication, due to profound
prior treatment warrants otherwise.34 induced immunosuppression.

Table 4 summarizes first- and second-line treatments by

Second-line treatment
disease stage, keeping in mind that no clear algorithm can
Mono- or polychemotherapy are the standard of care, together
be recommended.
with (in some highly selected patients) allogeneic stem-cell
transplantation as a rescue. The FDA recently approved the
Folliculotropic mycosis fungoides
histone deacetylase inhibitors romidepsin and vorinostat
This clinical and histological subtype of the disease has been
as second-line treatments in advanced CTCL. The ORR
reported for many years to have a worse prognosis. However,
has varied with the studies: from 30% with vorinostat35 to
the Dutch Cutaneous Lymphoma Group recently published
38% with romidepsin.36 The main AEs are gastrointestinal
a clinical staging system and consequently new treatment
and asthenic. These treatments are available in France, with
recommendations in this disease.42,43
temporary authorization of use.
Recently, targeted therapies have been developed and
Maintenance therapy
have shown promising results as second-line treatments in
When remission is achieved, maintenance therapy is recom-
these aggressive forms:
mended, keeping in mind the high importance of maintain-
• Brentuximab vedotin was recently approved by the ing the quality of life of patients suffering from this chronic
European Medicines Agency (EMA) for the treatment disease. Treatment agents that have shown some efficacy
of CD30-expressing CTCL as a second-line treatment, with tolerable side effects for this purpose are extracorporeal
according to the ALCANZA phase III study, show- photochemotherapy, IFNα, low-dose Mtx, mechlorethamine,
ing superiority to Mtx and bexarotene.37,38 The overall PUVA and UVB, retinoids, and topical corticosteroids.5 One
response rate in this study was 67% with brentuximab of the important aspects to take into account, because of its
vedotin vs 20% with treatment of physician’s choice. important impact on quality of life, is pruritus, which is often
This drug consists of the combination of an anti-CD30 improved by the treatment of MF, but sometimes requires a

2246 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11
Dovepress

Powered by TCPDF (www.tcpdf.org)

 Dovepress Denis et al

Table 4 Treatments available by disease stage

Stage or clinical First line Second line
presentation
IA: T1, N0 Expectant policy (T1a) In addition with skin-directed treatments:
Topical corticosteroids (T1a) • systemic therapies
Mechlorethamine gel • retinoids (re-PUVA++)
Localized RT (localized MF including pagetoid reticulosis) • IFNα
UVB (T1a) • low-dose Mtx
Photodynamic therapy • TSEB (T2b)
IB: T2, N0 Topical corticosteroids (T2a)
Mechlorethamine gel
UVB (T2a)
PUVA
IIA: T1–2, N1–2 PUVA
Mechlorethamine
IIB Systemic therapies Polychemotherapy
• retinoids Allogeneic stem-cell transplantation
• IFNα • CD30-expressing: brentuximab vedotin
TSEB
Monochemotherapy
Low-dose Mtx
±Localized (RT in combination)
IIIA–B Systemic therapies Monochemotherapy
• Retinoids Allogeneic stem-cell transplantation
• IFNα
TSEB
Low-dose Mtx
ECP (alone or combined)
IVA–IVB (pertinent ECP stage IVA 4–A
evidence insufficient Chemotherapy
to justify separation Radiotherapy (TSEB and localized)
between first- and Alemtuzumab (B2)
second-line treatment) Allogeneic stem-cell transplantation
Mogamulizumab
Sézary syndrome ECP retinoids or IFNα combined with ECP or PUVA Chemotherapy
Chlorambucil–prednisone Alemtuzumab
Low-dose Mtx Allogeneic stem-cell transplantation
Granulomatous slack Localized RT
skin
Folliculotropic MF (FMF) Same treatments according to stage, but poorer outcome: Advanced-stage FMF:
consider more aggressive treatment before unaggressive FMF: • local radiotherapy
• topical steroids • TSEB
• phototherapy • PUVA combined with local radiotherapy
Children6 Corticosteroids
UVB
PUVA
Abbreviations: RT, radiotherapy; MF, mycosis fungoides; UV, ultraviolet; PUVA, psoralen with UVA; Mtx, methotrexate; TSEB, total-skin electron beam; ECP, extracorporeal
photochemotherapy.

specific regimen. Mirtazapine and gabapentin have shown tumor‑growth pattern, and enhancing immunogenic host
efficacy in this indication.44 potential.10 NM treatment has evolved over the last few
years with regard to application site, vehicle method, and
What place for chlormethine gel? duration. Before 1980, topical NM was prepared in water,
Mechlorethamine or NM have been used in MF in the US and thus, owing to its instability, had to be applied immedi-
since 1949.5 This topical chemotherapy works as an alkyl- ately to the skin. The main AE of this aqueous preparation is
ating agent by affecting rapidly dividing cells, altering the hypersensitivity. In the early 1980s, an ointment preparation

Cancer Management and Research 2019:11 submit your manuscript | www.dovepress.com

2247
Dovepress

Powered by TCPDF (www.tcpdf.org)

 Denis et al Dovepress

of topical NM was introduced in the US. Several advantages In 2013, Lessin et al53 demonstrated in a randomized
were claimed: decreased risk of sensitization, decreased cost, multicenter blinded study the noninferiority of the gel prepa-
ease of application, and an emollient effect.11 In Europe, a ration in comparison with an ointment preparation (0.02%)
mechlorethamine solution (Caryolysine) was approved by the as second-line treatment in stage IA–IIA MF patients. Fol-
EMA in 1946, but since 2006 supply difficulties have made lowing this study, the treatment was approved by the FDA
its access impossible. A gel preparation was introduced and in 2013, in Israel in 2016, and in France in September 2017,
approved by the FDA in 2013,45 and since 2014 individual after temporary individual and then cohort authorization of
and then collective (2017) special authorization have allowed use since 2014. It offers the advantage of better adherence,
practitioners to prescribe this treatment in France.12 as the greasiness of the ointment was often highlighted.46

From aqueous preparation to gel Efficacy of mechlorethamine gel

Several studies have reported efficacy data on treatment In Lessin et al,53 a total of 260 patients randomly received
with mechlorethamine aqueous solutions. A recent review either the gel or the ointment form once daily for up to 12
­highlighted the difficulty in comparing them, as the frequency months. The CR rate was 13.8% in the gel arm and 11.5%
and duration of treatment varied, together with the use of in the ointment arm, and the overall response rate (partial
additional therapies.46 However, the complete response (CR) response [PR] + CR) was 58.5% in the gel arm and 47.7% in
rate reported was 51%–84% in T1 patients and 34%–62.2% the ointment arm. The gel arm had a time to 50% response of
in T2 patients.46 In most of these studies, topical NM was 26 weeks, while this was 42 weeks in the ointment arm. CR
not used alone, being associated with intralesional NM rates were lower than in previous studies with the aqueous
in tumors,47,48 localized radiotherapy,10,49 electron-beam solution and even with the ointment, probably because the
therapy,50 or phototherapy.51 use of concomitant therapies was not allowed in this study;
As reported earlier, the ointment preparation was 85.5% of patients in the gel arm had maintained response at
introduced in the 1980s in the US. Colleagues from the 12 months. Eight patients with MF variants (folliculotropic,
Stanford University clinic reported their experience using syringotropic, large-cell transformation) were included, and
this ointment in three main studies.11,49,50 In 1983,50 they four of six who ended the study showed a response. Fifteen
prospectively evaluated ointment-based mechlorethamine patients in the gel arm had progressive disease during follow-
(0.01%) in 43 patients with MF stage I–III, for a major- up. Among them, seven patients continued the treatment and
ity of patients after total-skin electron-beam therapy. The achieved a confirmed response later.
primary end point was to observe the development of Kim et al conducted an extension trial with 0.04%
allergic contact dermatitis (ACD) with this preparation. mechlorethamine gel for patients who had not achieved CR
However, they documented a CR in 17.6% for stage IA with the 0.02% formulation after 12 months.54 A total of 98
and 27.3% for stage IB patients. This decrease in efficacy patients were enrolled to apply the 0.04% gel once daily
with the ointment was explained by the authors as due to for 7 months, and 26 (26.5%) achieved a response (CR six,
the variation in concentration (0.001%–0.02%). In 1987, PR 20). No severe AEs were noted. In France, Mathieu et
they retrospectively reviewed 123 patients treated with NM al55 reported retrospectively the data of 107 patients treated
therapy (aqueous and ointment 0.01%–0.02%):49 they did during the “temporary authorization of use” from Decem-
not note any difference in efficacy between ointment and ber 2014 to December 2015. All patients were treated with
aqueous preparations (overall or relapse-free survival). chlormethine gel. Ninety-three percent of the patients were
However, 66% patients developed delayed hypersensitivity early-grade MF (50% IA, 37% IB, 6% IIA). For the majority
reactions (DHRs) with the aqueous preparation vs <5% with of patients (85%), the gel was applied three times weekly
the ointment. In 2003, they updated the long-term results, and as a second-line treatment. Topical corticosteroids were
reviewing 203 patients treated with aqueous and ointment- used as concomitant treatment in 77% of patients. The overall
based preparation at the same concentration (0.02%):11 the response rate was 57% (CR 7%, PR 50%).
CR rate was 65% in T1 and 34% in T2 patients. Similarly, From August 2014 to February 2017, data of 187 patients
no difference in terms of efficacy was observed between treated in France with mechlorethamine gel were reported,
the two preparations. However, the ointment was not used with an overall response rate of 79.2%. In the study by Lessin
in all the countries, especially not in France, because there et al,53 patients who used NM as maintenance therapy had
was no guarantee on stability.52 a longer response than those who did not.53 This effect of

2248 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11
Dovepress

Powered by TCPDF (www.tcpdf.org)

 Dovepress Denis et al

maintenance therapy was also reported in previous studies Systemic toxicity

with NM.11,51 However, the use of NM as maintenance therapy Systemic absorption was not detected in a phase II study53
is not mentioned by the FDA or Haute Autorité de Santé. evaluating 16 patients who received the gel formulation,
despite high-performance liquid chromatography serum
Safety assays. Moreover, no change in hematology values was noted.
The tolerance profile is not very different from the mechlor-
ethamine solution used for many years. During the trial by Les- Future directions
sin et al,53 no drug-related severe AE was reported. Data of the Further studies will be needed to assess the efficacy of mech-
patients treated with mechlorethamine gel from October 2014 lorethamine gel in association with other treatments. There are
to February 2017 in France were also published by the Haute no efficacy and safety data for mechlorethamine gel in children.
Autorité de Santé.12 During this period, 478 patients received
NM as second-line treatment, 93% of them to treat early-stage Conclusion
MF (IA–IIA). A total of 194 patients stopped the treatment, NM has been used for >50 years in MF. The mechlorethamine
135 (69.6%) for AEs, progression, or inefficiency. There were gel formulation is safe and has shown to be effective in early-
in total 182 pharmacovigilance reports concerning 450 AEs, stage MF refractory to first-line treatment. The main AEs
of which 81 were considered severe. The FDA also published involve the skin, and reducing the frequency of application
periodic reports of pharmacovigilance from the US, Rwanda, and using concomitant topical steroids can reduce the major-
Israel, and France: 2,071 AEs concerning 1,750 patients were ity of them. Moreover, the gel formulation is responsible for
reported, 188 (8.9%) of which were severe. These AEs were fewer DHRs than the aqueous solution. The gel formulation
related to hypersensitivity and skin side effects.12 allows treatment on an outpatient basis. This local treatment
can also be associated with systemic therapies in advanced-
Hypersensitivity reactions stage MF, due to the absence of systemic absorption of the
These include DHRs developed in skin side effects and immedi- product, although associations have to be evaluated. This
ate hypersensitivity, ie, urticaria. Anaphylactic-type reactions treatment is readily available in the US and Israel, with
following urticaria are of concern, and represent the most com- temporary authorization in France and in discussion in other
mon reason to stop the treatment and the only contraindication.46 European countries (especially Italy).

Skin side effects Disclosure

The most common side effects reported with mechloretha- The authors report no conflicts of interest in this work.
mine gel are ACD, DHRs, skin irritation, pruritus, erythema,
and hyperpigmentation. Hyperpigmentation is reversible in References
1. Willemze R. WHO-EORTC classification for cutaneous lymphomas.
most patients. Skin irritation is often managed by reducing Blood. 2005;105(10):3768–3785.
the frequency of application. In Lessin et al,53 it was higher in 2. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the
World Health Organization classification of lymphoid neoplasms. Blood.
the gel arm of the study, and 62% of patients reported a skin-
2016;127(20):2375–2390.
related AE. Patch testing was not systematically required, but 3. Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fun-
ACD was estimated to affect around 16.4% of the patients. goides. N Engl J Med. 2004;350(19):1978–1988.
4. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the stag-
This proportion of ACD was significantly lower than the ing and classification of mycosis fungoides and Sezary syndrome:
reported DHR incidence with the aqueous preparation. In the a proposal of the International Society for Cutaneous Lymphomas
(ISCL) and the cutaneous lymphoma task force of the European
French study, ACD was reported in around 20% of patients.55
Organization of Research and Treatment of Cancer (EORTC). Blood.
2007;110(6):1713–1722.
Secondary malignancies 5. Trautinger F, Eder J, Assaf C, et al. European Organisation for Research
and Treatment of Cancer consensus recommendations for the treatment
In Lessin et al, 20 nonmelanoma skin cancers were detected of mycosis fungoides/Sézary syndrome - Update 2017. Eur J Cancer.
in the 24-month follow-up period, of which only six were in 2017;77:57–74.
6. Wu M, Chang MD. Pediatric Mycosis Fungoides. NEJM J Watch.
treatment areas.53 Most appeared in sun-exposed areas and
2014;2014.
in patients with a history of skin cancer. This supports the 7. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and
results from a previous Danish study reporting no signifi- prognostic factors in mycosis fungoides/Sézary syndrome: validation of
the revised International Society for Cutaneous Lymphomas/European
cantly increased risk of nonmelanoma skin cancers in patients Organisation for Research and Treatment of Cancer staging proposal.
treated with NM.56 J Clin Oncol. 2010;28(31):4730–4739.

Cancer Management and Research 2019:11 submit your manuscript | www.dovepress.com

2249
Dovepress

Powered by TCPDF (www.tcpdf.org)

 Denis et al Dovepress

8. Photiou L, van der Weyden C, Mccormack C, Miles Prince H. Systemic 28. Trautinger F. Phototherapy of mycosis fungoides. G Ital Dermatol E
Treatment Options for Advanced-Stage Mycosis Fungoides and Sézary Venereol. 2017;152(6):597–606.
Syndrome. Curr Oncol Rep. 2018;20(4):32. 29. Wood GS, Wu J. Methotrexate and Pralatrexate. Dermatol Clin.
9. Zackheim HS, Kashani-Sabet M, Amin S. Topical corticosteroids 2015;33(4):747–755.
for mycosis fungoides. Experience in 79 patients. Arch Dermatol. 30. Quaglino P, Maule M, Prince HM, et al. Global patterns of care in
1998;134(8):949–954. advanced stage mycosis fungoides/Sezary syndrome: a multicenter
10. Ramsay DL, Halperin PS, Zeleniuch-Jacquotte A. Topical mechloretha- retrospective follow-up study from the Cutaneous Lymphoma Interna-
mine therapy for early stage mycosis fungoides. J Am Acad Dermatol. tional Consortium. Ann Oncol. 2017;28(10):2517–2525.
1988;19(4):684–691. 31. Zackheim HS, Kashani-Sabet M, Hwang ST. Low-dose methotrexate to
11. Kim YH, Martinez G, Varghese A, Hoppe RT. Topical nitrogen mustard treat erythrodermic cutaneous T-cell lymphoma: results in twenty-nine
in the management of mycosis fungoides: update of the Stanford experi- patients. J Am Acad Dermatol. 1996;34(4):626–631.
ence. Arch Dermatol. 2003;139(2):165–173. 32. Trautinger F, Just U, Knobler R. Photopheresis (extracorporeal photo-
12. LEDAGA. brief summary of the transparency committee opinion. 2017. chemotherapy). Photochem Photobiol Sci. 2013;12(1):22–28.
https://www.has-sante.fr/portail/upload/docs/application/pdf/2018-03/ 33. Virmani P, Zain J, Rosen ST, Myskowski PL, Querfeld C. Hematopoi-
ledaga_summary_ct16175.pdf. Accessed June 10, 2018. etic stem cell transplant for mycosis fungoides and sézary syndrome.
13. Heald P, Mehlmauer M, Martin AG, et al. Topical bexarotene therapy Dermatol Clin. 2015;33(4):807–818.
for patients with refractory or persistent early-stage cutaneous T-cell 34. Olsen EA, Rook AH, Zic J, et al. Sézary syndrome: immunopathogen-
lymphoma: results of the phase III clinical trial. J Am Acad Dermatol. esis, literature review of therapeutic options, and recommendations
2003;49(5):801–815. for therapy by the United States Cutaneous Lymphoma Consortium
14. Olsen EA, Hodak E, Anderson T, et al. Guidelines for phototherapy of (USCLC). J Am Acad Dermatol. 2011;64(2):352–404.
mycosis fungoides and Sézary syndrome: A consensus statement of the 35. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial
United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol. of vorinostat in patients with persistent, progressive, or treatment
2016;74(1):27–58. refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(21):
15. Stern RS, PUVA Follow-Up Study. The risk of squamous cell and basal 3109–3115.
cell cancer associated with psoralen and ultraviolet A therapy: a 30-year 36. Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multi-
prospective study. J Am Acad Dermatol. 2012;66(4):553–562. center, international, pivotal study of romidepsin in refractory cutaneous
16. Archier E, Devaux S, Castela E, et al. Carcinogenic risks of psoralen T-cell lymphoma. J Clin Oncol. 2010;28(29):4485–4491.
UV-A therapy and narrowband UV-B therapy in chronic plaque pso- 37. European Commission Approves ADCETRIS (brentuximab vedotin)
riasis: a systematic literature review. J Eur Acad Dermatol Venereol. for CD30-Positive Cutaneous T-Cell Lymphoma after One Prior Sys-
2012;26(Suppl 3):22–31. temic Therapy– Providing an Innovative Treatment Option to Patients.
17. Laws PM, Shear NH, Pope E. Childhood mycosis fungoides: experi- Available from: https://www.takeda.com/newsroom/newsreleases/2018/
ence of 28 patients and response to phototherapy. Pediatr Dermatol. european-commission-approves-adcetris-brentuximab-vedotin-
2014;31(4):459–464. for-cd30-positive-cutaneous-t-cell-lymphoma-after-one-prior-sys-
18. Specht L, Dabaja B, Illidge T, Wilson LD, Hoppe RT, International temic-therapy-providing-an-innovative-treatment-option-to-patients/.
Lymphoma Radiation Oncology Group. Modern radiation therapy Accessed April 23, 2018.
for primary cutaneous lymphomas: field and dose guidelines from the 38. Kim YH, Whittaker S, Horwitz SM. Brentuximab vedotin demon-
International Lymphoma Radiation Oncology Group. Int J Radiat Oncol strates significantly superior clinical outcomes in patients with CD30-
Biol Phys. 2015;92(1):32–39. expressing cutaneous T cell lymphoma versus physician’s choice
19. Quéreux G, Brocard A, Saint-Jean M, et al. Photodynamic therapy with (Methotrexate or Bexarotene): the phase 3 Alcanza Study. Blood.
methyl-aminolevulinic acid for paucilesional mycosis fungoides: a pro- 2016;128(22):182–182.
spective open study and review of the literature. J Am Acad Dermatol. 39. Kim YH, Bagot M, Pinter-Brown L. Anti-CCR4 monoclonal antibody,
2013;69(6):890–897. mogamulizumab, demonstrates significant improvement in PFS com-
20. Seyed Jafari SM, Cazzaniga S, Hunger RE. Photodynamic therapy as pared to vorinostat in patients with previously treated cutaneous T-cell
an alternative treatment for mycosis fungoides: a systemic review and lymphoma (CTCL): results from the phase III MAVORIC Study. Blood.
meta-analysis. G Ital Dermatol Venereol. 2018;153(6):827–832. 2017;130(Suppl 1):817–817.
21. Jones GW, Kacinski BM, Wilson LD, et al. Total skin electron radiation 40. Lundin J. Phase 2 study of alemtuzumab (anti-CD52 monoclonal anti-
in the management of mycosis fungoides: Consensus of the European body) in patients with advanced mycosis fungoides/Sezary syndrome.
Organization for Research and Treatment of Cancer (EORTC) Cutaneous Blood. 2003;101(11):4267–4272.
Lymphoma Project Group. J Am Acad Dermatol. 2002;47(3):364–370. 41. de Masson A, Guitera P, Brice P, et al. Long-term efficacy and safety
22. Elsayad K, Kriz J, Moustakis C. Total Skin Electron Beam for of alemtuzumab in advanced primary cutaneous T-cell lymphomas. Br
Primary Cutaneous T-cell Lymphoma. Int J Radiat Oncol. 2015; J Dermatol. 2014;170(3):720–724.
1;93(5):1077–1086. 42. van Santen S, Roach RE, van Doorn R, et al. Clinical Staging and Prog-
23. European Medicines Agency - Find medicine - Targretin. Avail- nostic Factors in Folliculotropic Mycosis Fungoides. JAMA Dermatol.
able from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/ 2016;152(9):992–1000.
medicines/human/medicines/000326/human_med_001078. 43. van Santen S, van Doorn R, Neelis KJ, et al. Recommendations
jsp&mid=WC0b01ac058001d124. Accessed April 23, 2018. for treatment in folliculotropic mycosis fungoides: report of the
24. Huen AO, Kim EJ. The role of systemic retinoids in the treatment of Dutch Cutaneous Lymphoma Group. Br J Dermatol. 2017;177(1):
cutaneous T-Cell lymphoma. Dermatol Clin. 2015;33(4):715–729. 223–228.
25. Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. 44. Demierre MF, Taverna J. Mirtazapine and gabapentin for reduc-
Dermatol Ther. 2003;16(4):311–321. ing pruritus in cutaneous T-cell lymphoma. J Am Acad Dermatol.
26. Zackheim HS, Kashani-Sabet M, Mcmillan A. Low-dose methotrexate 2006;55(3):543–544.
to treat mycosis fungoides: a retrospective study in 69 patients. J Am 45. VALCHLOR™ (mechlorethamine) [package insert]. Malvern, PA:
Acad Dermatol. 2003;49(5):873–878. Ceptaris Therapeutics, Inc.; 2013.
27. Aviles A, Neri N, Fernandez-Diez J, Silva L, Nambo MJ. Interferon and 46. Liner K, Brown C, Mcgirt L. Clinical potential of mechlorethamine gel
low doses of methotrexate versus interferon and retinoids in the treat- for the topical treatment of mycosis fungoides-type cutaneous T-cell
ment of refractory/relapsed cutaneous T-cell lymphoma. Hematology. lymphoma: a review on current efficacy and safety data. Drug Des
2015;20(9):538–542. Devel Ther. 2018;12:241–254.

2250 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11
Dovepress

Powered by TCPDF (www.tcpdf.org)

 Dovepress Denis et al

47. van Scott EJ, Kalmanson JD. Complete remissions of mycosis fungoi- 53. Lessin SR, Duvic M, Guitart J, et al. Topical chemotherapy in
des lymphoma induced by topical nitrogen mustard (HN2). Control of cutaneous T-cell lymphoma: positive results of a randomized, con-
delayed hypersensitivity to HN2 by desensitization and by induction trolled, multicenter trial testing the efficacy and safety of a novel
of specific immunologic tolerance. Cancer. 1973;32(1):18–30. mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol.
48. van Scott EJ, Winters PL. Responses of mycosis fungoides to 2013;149(1):25–32.
intensive external treatment with nitrogen mustard. Arch Dermatol. 54. Kim YH, Duvic M, Guitart J, et al. Tolerability and efficacy of Mech-
1970;102(5):507–514. lorethamine 0.04% gel in CTCL (Mycosis Fungoides) after initial
49. Hoppe RT, Abel EA, Deneau DG, Price NM. Mycosis fungoides: treatment with topical Mechlorethamine, 0.02% gel. Presented at the
management with topical nitrogen mustard. J Clin Oncol. 1987;5(11): T-cell Lymphoma Forum. 23-25 January 2014; San Francisco, CA, USA.
1796–1803. Poster number TS14-1.
50. Price NM, Hoppe RT, Deneau DG. Ointment-based mechlorethamine 55. Mathieu S, Ram-Wolff C, Baylot-Barry M, D’Incan M, Bagot M.
treatment for mycosis fungoides. Cancer. 1983;52(12):2214–2219. L’expérience française de l’usage du gel de chlorméthine pour le
51. Zachariae H, Thestrup-Pedersen K, Søgaard H. Topical nitrogen mustard traitement du mycosis fongoïde: une série rétrospective de 107 cas
in early mycosis fungoides. A 12-year experience. Acta Derm Venereol. du GFELC [The French experience of the use of chlormethine gel
1985;65(1):53–58. for the treatment of mycosis fungoides: a retrospective series of 107
52. Beylot-Barry M, Dereure O, Vergier B, et al. Prise en charge cases of GFELC]. Ann Dermatol Vénéréologie. 2016;143(12):S155.
des lymphomes T cutanés: recommandations du Groupe fran- French.
ç a i s d ’ é t u d e d e s ly m p h o m e s c u t a n é s [ M a n a g e m e n t o f 56. Lindahl LM, Fenger-Grøn M, Iversen L. Secondary cancers, comorbidi-
cutaneous T-cell lymphomas: Recommendations of the French Cuta- ties and mortality associated with nitrogen mustard therapy in patients
neous Lymphoma Group]. Ann Dermatol Vénéréologie. 2010;137(10): with mycosis fungoides: a 30-year population-based cohort study. Br
611–621. French. J Dermatol. 2014;170(3):699–704.

Cancer Management and Research Dovepress

Publish your work in this journal
Cancer Management and Research is an international, peer-reviewed a very quick and fair peer-review system, which is all easy to use. Visit
open access journal focusing on cancer research and the optimal use of http://www.dovepress.com/testimonials.php to read real quotes from
preventative and integrated treatment interventions to achieve improved published authors.
outcomes, enhanced survival and quality of life for the cancer patient.
The manuscript management system is completely online and includes
Submit your manuscript here: https://www.dovepress.com/cancer-management-and-research-journal

Cancer Management and Research 2019:11 submit your manuscript | www.dovepress.com

2251
Dovepress

Powered by TCPDF (www.tcpdf.org)