NON SURGICAL MANAGEMENT OF CUTANEOUS
MALIGNANCIES
Lip Teh
Imiquimod
Developed to treat genital warts
Aldara (5% cream)
immune response modifier
acts through the toll-like receptor (TLR) 7 - ↑IFN alpha
induces a significant lesional lymphocytic inflammation
enhance Th1-mediated cellular antiviral and antitumor immunity
Effect of imiquimod on inflammatory cells. Secretion of IL-12 by antigen-presenting
cells induces IFN-gamma secretion by naive T cells during cell-cell interactions and
results in the development of a Th1-lymphocyte-mediated immune response. GM-CSF
= granulocyte-macrophage colony-stimulating factor; IL = interleukin; APC =
antigen-presenting cell; MCP = monocyte chemotactic protein; TLR7 = toll-like
receptor-7; Th2 = T-helper cell type 2; NF-kappaB = nuclear factor kappa B; PMN
= polymorphonuclear neutrophil; Th1 = T-helper cell type 1; TNF = tumor necrosis
factor; MIP = macrophage inflammatory protein; IFN = interferon; MIG-CSF =
granulocyte colony-stimulating factor; NK = natural killer cell.
Dermatological indications
1) BCC
a. Superficial/nodular BCC subtypes
2)
3)
4)
5)
6)
7)
b. 5-6x/week for 6 weeks (up to 16weeks)
c. Composite clearance rates (combined clinical and
histological assessments) - 75% (phase III)
d. ?Useful in Gorlins (1 case report – 3 patients, all lesions
cleared)
Bowens disease
a. 5-6x/week for 6 weeks up to 16weeks
b. Efudex better – more predictable and less scarring
Actinic keratosis
a. 2x/week for 6 weeks
b. 57% complete clearance rate (n=286 phase III)
Scars (PRS March 2005)
a. 2x/week for 8 weeks, 2 months post-op
Cutaneous melanoma mets
Lentigo maligna (case reports)
Herpes Simplex, molluscum contagiosum, aphthous ulcers,
mycosis fungoides, hemangiomas, warts
Side effects
1) Pain (chronic neuropathic pain case report)
2) Erythema, itching, ulceration, scaling, crusting
3) Headache
4) Hypopigmentation
5) Atrophic scar – may be worse than surgery
Avoid facial areas due to hypopigmentation and scarring.
Increasing severity of erythema, erosion, and scabbing/crusting associated
with higher clearance rates.
5-fluorouracil
Developed in 1957 for intestinal tumours.
Efudex 2% or 5% cream or solution
Fluoroplex 1% cream
Carac 0.5% cream
fluorinated pyrimidine
antimetabolite
metabolized intracellulary to its active form, fluorodeoxyuridine
monophophate
The active form inhibits DNA synthesis by inhibiting the normal
production of thymidine.
cell cycle phase-specific (S-phase).
Related Indications:
1) Actinic keratosis/SCC in-situ
a. 80%-100% complete clearance
b. Twice daily for 3 weeks face and 3-6 weeks elsewhere
2) Superficial BCC
a. 91% complete composite clearance with intralesional
application (n=122 J Am Acad Dermatol. 1997 Jan;36(1):72-7.)
b. Topical – 20% clearance
3) Lentigo maligna (case reports)
4) Keloids – 1 touch treatment
5) Tendon adhesions – 1 touch treatment
Contraindications
1) Hypersensitivity
2) dihydropyrimidine dehydrogenase (DPD) enzyme deficiency
Side effects
1) progressive inflammation, erythema, and erosions
2) Contact dermatitis with intense pruritis (usually happens Day 1)
3) photosensitivity
4) Hypopigmentation uncommon
Intralesional Interferon
Intralesional recombinant interferon alpha-2 injections
Indications:
1) BCC
a. Injected 3x/week for 3weeks
b. 86% histological cure rate (n=172) - use 1.5munits/cm2
mechanism of action:
an antitumour inflammatory infiltrate
intensifying the expression of the tumour antigens
inhibiting cell proliferation
increasing apoptosis of BCC cells
Side effects (75% have at least 1)
1) Headache
2) fever, myalgia, arthralgia, malaise, and nausea
Retinoids
Isotretinoin (roaccutane) – more for acne
Acitretin (mainly used for skin cancers)
Tazarotene – topical, a new acetylenic retinoid.
ability to maintain epithelial cell differentiation and modify cell growth and
differentiation.
mechanisms of action:
principally responsible for differentiation of epithelial tissues
act as hormones, and interact with retinoic acid receptors and retinoid X
receptors in the cell nucleus.
1) Stimulate mitotic activity and increase follicular cell turnover
2) Corticosteroid-like mechanism (eg, anti-inflammatory)
3) Affect posttranslational glycosylation
4) Disrupt tumor cell membrane
5) Liposomal enzyme release
6) Suppress ornithine decarboxylase (ie, DNA synthesis inhibition)
7) Immunostimulation of T-killer cells
Indications
1) Actinic keratosis
2) SCC (main indication)
3) BCC
a. Not useful but reported 47% cure with topical tazarotene
4) Acne, psoriasis, and disorders of cornification
Chemoprophylaxis
1) Southwest Skin Cancer Prevention Study Group
a. daily supplementation with 25,000 IU of retinol was effective
in preventing SCC, although it did not prevent BCC in
moderate risk group
2) Renal transplant patients
a. Low dose prophylaxis 10-25mg/day
b. 40%-50% reduction in keratotic lesions with acitretin. Does
not prevent BCC
3) Xeroderma pigmentosa
a. High dose Isotretinoin - 60% reduction in skin cancers
4) Isotretinoin-Basal Cell Carcinoma Study Group 1992
a. long-term administration of low-dose isotretinoin
b. ineffective with significant side effects
acitretin is used routinely in renal transplant patients for chemoprophylaxis.
Side effects
common – significant number withdraw
1) Headaches
2) Hyperlipidaemia (need to monitor LFTs, lipids)
3) Rash
4) Arthralgia/Myalgia
5) Mucosal dryness
6) Alopecia
7) Teratogenic
Systemic Chemotherapy
Reserved for treating locally advanced or metastatic forms of NMSC.
Significant side effects and poor efficacy
Drugs: cisplatin, doxorubicin, 5-FU, and mitomycin C
Cisplatin most common - often combined with 5-FU or doxorubicin.
Cryotherapy
Indications:
reserved for smaller, clearly demarcated lesions, but it may be appropriate
for patients with large superficial tumors, multiple tumors, or tumors within
scars in low-risk sites
A study of 563 primary SCCs between 0.5 and 1.2 cm in diameter suggested
a cure rate of 97.3%, and a recent analysis indicated that the overall 30-year
cure rate was 98.6% in more than 2000 patients with new and recurrent
BCC and SCC. However, the patients included in this analysis were all
treated by the same highly skilled physician.
More typical 5-year cure rates for primary BCC are around 93%.
Contraindications :
1) tumors with poorly defined borders
2) invasive SCC
3) aggressive subtypes of BCC
4) recurrent skin cancers
5) tumors in hair-bearing skin (alopecia)
Mohs Micrographic Surgery
The technique involves
1) tumor excision
2) mapping of the removed tissue
3) immediate microscopic assessment of the surgical specimen.
Indications:
1) recurrent tumors
2) incompletely excised tumors
3) larger than 2 cm
4) indistinct margins or aggressive histology
5) in areas with high propensity for recurrence and metastasis
6) tumors in areas where maximal tissue conservation is required
Disadvantages
1) High costs
2) Intensive process
Curative for 99% of primary BCCs and 97% of primary SCCs -- highest
documented cure rates.( Clin Dermatol 1995)
Recurrent SCC, 5-year cure rates of 90% -93.3%, vs 76.7% treated with
standard excision. (J Am Acad Dermatol 1992)
Radiotherapy
electron beam therapy (better for contoured surfaces) vs. superficial x-ray
therapy
Roles: definitive, adjuvant and palliative
Target lesions: keratoacanthomas, extensive actinic keratoses, Bowen's
disease including erythroplasia of Queyrat, basal cell and squamous cell
carcinomas, lentigo maligna and lentigo maligna melanomas. Less effective
in Kaposi’s sarcoma, mycosis fungoides and Meckell Cell carcinoma.
NMSC (Int J Radiat Oncol Biol Phys. 2001):
overall local tumor control rate 89%;
93% for previously untreated lesions
80% for recurrent lesions.
basal cell carcinoma - 92% overall control rate; squamous cell
carcinoma 80%
Four-year locoregional controls for advanced BCC and SCC are 86% and
58%, respectively.( Int J Radiat Oncol Biol Phys. 2004)
Peter MacCallum Cancer Institute (1989):
Superficial radiotherapy was associated with a 2.3-fold increase in failure rate
compared to surgery
Adjuvant radiotherapy for Meckel Cell carcinoma – standard practice
1) Cumulative data from small retrospective series have supported
treatment by wide excision and adjuvant radiotherapy.
2) Combination therapy vs surgery alone (Oncol Rep. 2003)
a. locoregional control (65% compared to 43%)
b. relapse-free survival (88 versus 58 months)
3) Adjuvant radiation to primary site appears unessential to secure local
control of primary MCC lesions completely excised with Mohs
micrographic surgery. (J Am Acad Dermatol. 2002)
Photodynamic Therapy
Photodynamic therapy (PDT), also called photoradiation therapy,
phototherapy, or photochemotherapy, is a treatment that combines a light
source and a photosensitizing agent to destroy susceptible cells.
Approved by FDA for cancer of the esophagus(1995) and non-small cell
lung cancer (1998), and actinic keratosis(1999).
Because the approved light sources can only penetrate a limited depth
through tissue, PDT is mainly used to treat areas on or just under the skin,
or in the lining of internal organs.
Trials underway for PDT vs surgery/radiation therapy.
Potential advantages: fewer side effects and therapy can be repeated several
times at the same site if necessary.
Theory
PDT is mediated by oxygen-dependent photochemical reactions.
Upon absorption of photons of light, the photosensitizer is excited to a
short-lived singlet state followed by a transition to the reactive triplet state.
From its triplet state in the presence of oxygen, reactive free radicals and
singlet oxygen species ensue. These, in turn, react with cell membranes,
causing direct damage to the mitochondria, endoplasmic reticulum, and/or
plasma membranes.
Indirect effects on the normal microvasculature and the inflammatory and
immune host system.
1)vascular effects include vasoconstriction of the arterioles within the
tumor, reduction of the erythrocyte flow velocity in the venules of the
surrounding tissue, blood stasis, and thrombosis of the tumor vessels
leading to ischemia and subsequent tumor necrosis.
2) Immunologic effects include the production of IL- 1 beta, IL 2, TNF-a,
and G-SF
Photosensitizers can be attacked by singlet oxygen or free radicals, leading
to their inactivation in a phenomenon known as photobleaching. This effect
may be useful in normal skin where low levels of the drug are
photobleached instead of photoactivated, while within the diseased tissue,
where drug levels are higher, photodynamic reactions predominate. The
result is a higher therapeutic ratio. As most photosensitizers do not
accumulate in cell nuclei, PDT generally has a low potential for causing
DNA damage, mutations, and carcinogenesis.
Procedure
1) The photosensitizer is administered to the patient (eg, topical, oral,
intravenous).
2) activation of the photosensitizer in the presence of oxygen with a specific
wavelength of light directed toward the target tissue. Because the
photosensitizer is preferentially absorbed by hyperproliferative tissue and
the light source is directly targeted on the lesional tissue, PDT achieves dual
selectivity, minimizing damage to adjacent healthy structures.
Agents
1st Generation Agents
1)Photofrin (or porfimer sodium, esthers of hematoporphyrin-IX )
IV - dose of 0.5-2 mg/kg, and light exposure is carried out 24-72 hrs later.
Optimum absorption peak 630-nm
The main disadvantage is prolonged cutaneous photosensitivity, which lasts
for 4-6 weeks or even several months because of its relatively slow rate of
clearance from the skin.
2)5-Aminolevulinic acid
ALA is the first intermediate in the biosynthetic pathway of heme. When
given in excess, ALA drives heme synthesis until intracellular iron is
depleted; causing accumulation of a heme precursor protoporphyrin IX
(PpIX) in the cells. PpIX is a moderately potent photosensitizer with an
optimum absorption peak at 635 nm.
Short half life - photosensitivity resolves within 24 hours.
Because of its low molecular weight, ALA can be topically applied to the
skin lesions, eliminating generalized photosensitivity. PpIX can be detected
4 hours after topical application of ALA.
for skin lesions - application of 5-20% ALA in an oil-in-water emulsion with
or without occlusion.
Lesions are exposed to either blue light or light at 630-635 nm 3-6 hours after
application (i.e not laser).
2nd Generation Agents
1)Benzoporphyrin derivative monoacid ring A
BPD-MA is a chlorin synthesized from protoporphyrin.
Absorption peak at 690 nm.
Deeper tissue penetration compared with applications at 630-635 nm as
used with ALA. Peak tissue levels are reached 3 hours after injection, with
50-60% tissue clearing in 48 hours.
Cutaneous photosensitivity usually lasts less than 1 week.
Trials with BPD-MA for age-related macular degeneration, skin cancer, and
psoriasis are ongoing.
2)Tin ethyl etiopurpurin
SnET2 is a synthetic chlorophyll analogue with an absorption peak at 660
nm. The drug dose is usually 1-1.6 mg/kg, and light treatment is given 24-72
hours after injection. SnET2 has been successfully used for the treatment of
basal cell carcinoma (BCC), Bowen disease (BD), Kaposi sarcoma, and
cutaneous metastases.
3)Lutetium texaphyrin
Lu-tex - highly fluorescent dye
Absorption peak at 732 nm.
Drug doses of 0.6-7.2 mg/kg are systemically administered 3 hours prior to
light treatment. Lu-tex appears to be highly selective for tumors rather than
normal skin. Early reports show that complete response of subcutaneous
melanoma with minimal damage to the overlying skin can occur.
Currently, 5-ALA is the only agent used for skin cancers in WA
Light Sources
Lasers
purpose of lasers in PDT is to initiate photochemical reactions and not for
photothermal or photomechanical effects
Lasers used include gold vapor laser (628 nm) and tunable dye lasers
pumped by argon ions, copper vapor, Nd:YAG or potassium-titanylphosphate (KTP), and excimer lasers.
Semiconductor diode lasers, which are more powerful, smaller, and cheaper
than other lasers, are commercially available at wavelengths useful for many
PDT applications and may become the light source of choice in the future.
Advantages of lasers:
1) monochromaticity - maximum effectiveness if the wavelength of the laser
corresponds with the peak absorption of the photosensitizer.
2) produce high irradiance to minimize the therapeutic exposure time.
3) can be readily coupled to fiberoptics
Noncoherent light sources
Given the right dose of drug and light, noncoherent light sources appear to
be every bit as effective as laser sources. Most common - 640 nm (red light)
and 400-450 nm (blue light)
Advantages over laser
1)larger treatment field esp for skin lesions
2) low cost, smaller size, and ready availability.
3) polychromatic light sources allow the use of different photosensitizers
with different absorption peaks. Sources emitting both 635 nm and 670 nm
could improve the effectiveness of ALA-PDT because photoproducts of
PpIX, can also be activated by light at about 670 nm.
Dosimetry
fluorescence emission can be monitored by using in vivo
spectrophotofluorimetry. Photobleaching can also be monitored by means
of the fluorescence signal.
Treatment in Skin conditions
At present, topical 5-ALA is the most promising PDT agent for many
dermatologic uses.
The major limitation of topical ALA-PDT is its depth of treatment, which
appears to be mainly the result of the failure to achieve adequate ALA
penetration rather than light penetration.
Greater uptake and a greater effective depth for ALA-PDT could be
obtained by increasing the application or occlusion times or by adding
penetration enhancers (eg, DMSO, EDTA).
Iron chelators (eg, desferrioxamine) enhance PpIX formation by interfering
with the heme cycle.
In addition, iontophoresis can be used to drive ALA, a charged molecule,
into the skin.
Benign skin conditions
Psoriasis
Silver(1937) used the systemic administration of hematoporphyrin in
combination with ultraviolet radiation.
Berns et al confirmed the effectiveness of hematoporphyrins administered
systemically followed by 630-nm illumination..
Boehncke - combining intravenous administration of BPD with 600- to 700nm light for a total of 5 weeks. All patients exhibited partial responses as
early as 2 weeks after initiating treatment.
Human papilloma virus–associated skin diseases
The selective PpIX fluorescence distribution in condylomata acuminata after
topical application of ALA suggests the potential use of ALA-PDT to treat
this condition. Stender et al reported good results of recalcitrant hand and
foot warts treated with 20% topical ALA, followed 4 hours later with 70
J/cm2 of red light (590-700 nm) irradiation.
Vascular malformations
Successful treatment of a capillary hemangioma with hematoporphyrin
derivative (HpD)–PDT was described in 1985. Recently, Lin et al reported
130 patients with port-wine stains (PWS) who were treated with PsD-007, a
purified mixture of 6 kinds of porphyrin molecules, and a 578-nm copper
vapor laser. In the macular PWS group; 37.8% of the cases were categorized
as excellent; 53.7%, as good; 8.5%, as fair; and 0%, as poor after a single
treatment. However, only 33.3% of the hypertrophic group had an excellent
or good response.
Disorders of pilosebaceous units
The finding that PpIX generated after the administration of ALA
accumulates not only in epidermal cells but also in pilosebaceous units has
led to studies of topical PDT in hirsutism and acne. Disorders of the
sebaceous glands, such as sebaceous gland hyperplasia and rhinophyma,
appear to be other potential indications for the use of ALA-PDT.
Premalignant skin conditions
Actinic keratoses
Complete response rates following topical ALA-PDT= 90%. (n=243 phase
III)
The poor clinical response of thick hyperkeratotic lesions may be due to the
ineffective penetration of ALA and the consequent lack of conversion to
PpIX. Compared with the application of topical 5-fluorouracil (5-FU) twice
daily for 3 weeks, a single treatment with topical ALA-PDT appeared to be
as effective and well tolerated.
Malignant skin conditions
Bowen disease
BD is highly responsive to systemic PDT. Robinson et al treated more than
500 lesions of BD in 2 patients with 1.5-2 mg/kg of HpD and a 628-nm
wavelength pulsed gold vapor laser (25 J/cm2). A complete response rate of
100% with less than 10% of the lesions requiring a second treatment was
achieved. A similar result was achieved with 1 mg/kg porfimer sodium and
an argon dye laser at 185-250 J/cm2. A number of studies reported that
topical ALA-PDT for the treatment of BD has produced complete response
rates of 90-100%.
Invasive squamous cell carcinoma
Only a few reports of the use of PDT for invasive squamous cell carcinomas
(SCCs) exist, and recurrence rates seem unacceptably high (50%).
Pennington et al reported an initial clearance rate of 81% with HpD for 32
SCCs, but it decreased to less than 50% at the 6-month follow-up visit.
Another study reported a complete response rate of 40% at 12 months after
treating 5 SCCs with HpD and porfimer sodium. However, in both studies,
the light doses used were low (20-30 J/cm2). For topical ALA-PDT, the
complete response rate was 67-100% for superficial SCCs and 0-33% for
nodular SCCs. So far, few invasive SCCs have been treated with ALA-PDT.
Further studies are required before conclusions can be drawn.
Basal cell carcinoma
Feyh reported a histologically controlled study with biopsy samples obtained
2 months after treating 57 BCCs with HpD (2 mg/kg) and a 630-nm argon
pumped dye laser (100 J/cm2). Of 57 lesions, 51 showed a complete
response. Wilson et al treated 151 BCC lesions in 37 patients with porfimer
sodium (1 mg/kg) and a 630-nm argon pumped dye laser (72-288 J/cm2). A
complete response rate of 88% was achieved with one treatment at 3
months. In this study, partially responsive lesions that underwent repeat
treatment achieved a complete response.
Subsequent studies with topical ALA-PDT reported a cure rate of 79-100%
for superficial BCCs and 10-71% for the noduloulcerative form. Pigmented
BCCs were resistant to treatment. Topical ALA fails to induce detectable
PpIX in morpheaform BCCs and may only partially sensitize nodular
lesions. This result implies a higher recurrence rate for morpheaform and
nodular BCCs after PDT treatment. Lengthening the application of ALA to
6 hours rather than 4 hours significantly increases the complete response
rate for superficial BCCs from 70% to 100%.
Repeated treatment and prior debulking techniques can improve the
effectiveness of topical ALA-PDT for BCCs.
Recently, a prospective phase III clinical trial study was completed to
compare ALA-PDT and cryotherapy in the treatment of BCCs. The
effectiveness of ALA-PDT is comparable with that of cryosurgery as a
treatment modality for BCCs. The advantages of ALA-PDT are a shorter
healing time, less scarring, and better cosmetic outcome. Morton et al
succeeded in treating 40 large BCCs (>20 mm in diameter) with an initial
clearance rate of 88% after 1-3 treatments and 4 recurrences within 34
months (range, 12-60 mo). He proposed topical ALA-PDT as the first-line
therapy for large BCCs or multiple areas with superficial BCCs.
Malignant melanoma
The absorption of light by melanin makes cutaneous melanomas poor
targets for PDT. However, newer photosensitizers with a longer peak
excitation wavelength (eg, such as BPD-MA) have shown a positive
response in animal trials. The response may be enhanced by pretreatment
with a Q-switched Nd:YAG laser, which causes a selective breakdown of
melanosomes.
Complications
burning, stinging, pruritus, pain during tretment.
- direct nerve stimulation and/or damage by reactive singlet oxygen
and released mediators.
- usually well tolerated, and local anesthesia is seldom required.
hyperpigmentation and hypopigmentation
- most common adverse effects (usually transient)
Local edema and erythema
Blistering, ulceration
Generalized cutaneous photosensitivity
- The severity and duration of photosensitivity depend on the type
and dose of photosensitizer.
-The reactions range from mild burning or stinging to severe edema,
erythema, and bulla formation.
- Because the action spectrum for this phototoxicity is in the visible
range, chemical sunscreens are of no benefit. Protective clothing
and strict avoidance of bright direct light are recommended. The
use of topical photosensitizers circumvents the problem of
prolonged photosensitivity.
- photophobia and/or ocular discomfort. All patients should wear
protective eyewear for several weeks after PDT with porfimer
sodium.