Khối U Ác Tính Dưới Da: Góc Nhìn Phẫu Thuật (Cutaneous Malignancies)

patients who received lymph node dissection for primary SCC
located on the trunk or extremities, postoperative RT is typi-
cally recommended when multiple nodes are involved or
extracapsular extension is present. Similar to mucosal SCC of
Fig. 7.8 A 75-year-old woman with a neglected T4 basal cell carcinoma of the scalp. (a) Preoperative disease. (b) Postoperative results after free flap
reconstruction and postoperative radiation therapy. (c) Postoperative radiation plans (axial, sagittal, and coronal planning CT scans) demonstrating
radiation dose distribution.
Fig. 7.9 A 91-year-old man with a history of extreme kyphosis and
multiple facial SCC, who presented with a rapidly enlarging right neck
mass, treated with surgical resection and free flap reconstruction.
(a) Axial slice depicting isodose coverage of the neck bed with electron
radiation therapy. (b) Extreme kyphosis dose coverage using 30 Gy in
five fractions twice weekly.
Fig. 7.10 A 63-year-old man with multiple recurrent SCC of the right
temple with Mohs map overlying the site of the tumor.
Role of Radiotherapy in the Treatment of Skin Malignancies
138

the head and neck, RT can be avoided in immunocompetent
patients with a single involved lymph node, smaller than 3 cm,
without extracapsular extension on parotidectomy or cervical
lymph node dissection, as rate of regional recurrence is less
than 5%.22
PNI, while not com mon (5–10% of SCC), is another impor-
tant risk factor for recurrence that should be weighed in the
decision to adm inister adjuvant RT. PNI is typically divided
into clinical and microscopic PNI. Clinical PNI is defined by
neurologic m anifestations, m ost com m only involving the tri-
gem inal or facial nerves, leading to pain, paresthesias, para-
lysis, formication (the sensation of bugs crawling on the
skin), or radiographic evidence of nerve enhancement.23,24
Microscopic PNI is appreciated only histologically and is
identified after surgery in a patient who was asymptom atic
preoperatively. PNI is important given it is associated with
increased risks of local recurrence as well as regional and
distant m etastases. Factors associated with increased risk for
SCC w ith PNI include male sex, tum or size greater than
2 cm, m idfacial tumor location, recurrent tum or, and poorly
di erentiated subtypes.25 The degree of PNI is predictive of
risk of recurrence; therefore, a careful history as well as
physical and im aging examination is critical. Magnetic reso-
nance imaging (MRI) has the advantage of identifying the
extent of m acroscopic disease through nerve enlargement or
enhancement or obliteration of the norm al fat plane sur-
rounding a nerve ( Fig. 7.12). CT o ers the advantage of
detecting whether bone erosion is present, particularly
tum or invasion into foramina associated w ith cranial nerves.
The di erence between clinical and microscopic PNI was
highlighted in a series from the University of Florida which
compared the outcom es of patients with PNI treated aggres-
sively w ith surgery and postoperative RT. Those w ith clinical
PNI had significantly lower 5-year rates of local control
(57 vs. 90%; p = < 0.001) and overall survival (57 vs. 69%;
p = 0.03) compared to those found to have microscopic
PNI.13,23 RT is therefore always recomm ended in cases of
clinical PNI. The role of postoperative RT in patients w ith
pathologic PNI is less clear. Lin et al found that focal versus
extensive m icroscopic PNI carries di erent prognoses, with
relapse-free survival better in the former group (86 vs. 74%;
p = 0.1).24 Unfortunately, the distinction between focal and
extensive was not well defined. As such, adjuvant RT is not
recomm ended in im m unocompetent patients with nonrecur-
rent disease, in whom one or two isolated areas of PNI are
found in sm all unnam ed nerves, with a diam eter of less
than 0.1 m m, given the outcome is expected to be fairly
good with surgery alone. However, patients with m icro-
scopic PNI, that is m ultifocal, involves larger nerves
(> 0.1 m m in diam eter) and nam ed nerves, or occurs in
im m unosuppressed patients, are at higher risk and thus
adjuvant RT is recom m ended.2,25
For irradiation of clinical PNI, the clinical target volume
should include areas at high risk of failure, specifically the
involved nerve, the portion of the nerve proxim ally at the
skull base, the distal skin innervated by the nerve, major
comm unicating branches, and the compartm ent in w hich
the nerve is em bedded.26 For example, for patients with CN
VII involvem ent, the area of treatm ent should be tracked
back to the nerve’s exit through the stylomastoid foram en,
with care taken to adm inister adequate coverage of the gen-
iculate ganglion by avoiding excessive restriction of the radi-
ation dose delivered to the ipsilateral cochlea. Sim ilarly,
with V1/V2 nerve involvem ent, the gasserian ganglion in
Meckel cave and the cavernous sinus should be targeted
( Fig. 7.13). Targeting the nerve root as it exits the brain-
stem should be considered for nerves that are radiographi-
cally involved at the skull base. For patients with
unresectable disease invading the skull base, high-dose radi-
ation (70 Gy), with or w ithout concurrent chem otherapy, is
required ( Fig. 7.14).
Another consideration highly relevant to radiation field
design is the observation that PNI may also be associated
with increased nodal failure in addition to recurrence in the
tumor bed and along the nerve pathway. Lin et al demon-
strated that patients who developed recurrent disease with
pathologic PNI had a significantly higher risk of local recur-
rence (40 vs. 19%; p <0.01) as well as regional recurrence (29
vs. 5%; p =0.02).24 It is important to consider the location of
the lesion in such scenarios, given that tumors on the scalp,
for example, may be less likely to metastasize to lymph
nodes, compared to cheek, ear, or nasal skin lesions. Under-
standing the drainage patterns of these tumors is crucial (e.g.,
parotid nodes for head and neck sites, axilla for trunk and
extremity lesions) and should be incorporated into radiation
targeting.
Fig. 7.11 (a) Coronal CTslice of dose distribution
for postoperative radiation therapy after Mohs
surgery for tumor depicted in Fig. 7.10.
(b) Coronal slice of dose distribution for post-
operative radiation therapy covering the ipsi-
lateral cervical lymph nodes.
Role of Radiotherapy in the Treatment of Skin Malignancies
139

Fig. 7.13 (a) Axial radiation planning CT slice
depicting inferior alveolar nerve (solid red)
covered by isodose lines. (b) Axial radiation
planning CT slice depicting left cavernous sinus
and temporal musculature (solid light blue)
covered by isodose lines. (c) Axial radiation
planning CT slice depicting course of V2 into
cavernous sinus (solid red) covered by isodose
lines. (d) Sagittal radiation planning CT slice
depicting coverage of V1 and V2 back to the
cavernous sinus (solid red) covered by isodose
lines.
Fig. 7.14 (a) A 67-year-old man with history of
recurrent right auricular SCC treated with multi-
ple surgical resections and prior irradiation who
presented with recurrent disease at the right skull
base (red arrow). (b) Sagittal radiation planning
CT slice depicting recurrent disease covered by
70 Gy isodose line (black line).
Fig. 7.12 A 64-year-old man with a history of
chronic immunosuppression and pT2N0 SCC of
left temple treated with surgery, with recurrence
involving the trigeminal nerve. (a) Left V3 nerve
enhancement is demonstrated at the foramen
ovale (red arrow). (b) Left V2 enhancement is
demonstrated at the infraorbital nerve (red
arrow), with tracking back into Meckel’s cave. He
received post-salvage surgery IMRT with concur-
rent cetuximab with no evidence of disease at 8-
month follow-up.
Role of Radiotherapy in the Treatment of Skin Malignancies
140

7.2.2 Indications for Radiotherapy for
Cutaneous Melanoma
Indications for Definitive Radiotherapy
Melanoma is believed to be a relatively radioresistant malig-
nancy. Therefore, maximal surgical resection is paramount in
the management of these tumors. RT has limited benefit in
achieving long-term control in the presence of gross disease. RT
is delivered to gross melanoma in patients deemed to have
unresectable disease, or those with rapid postoperative recur-
rence who have failed surgical management. In these cases,
higher doses per fraction are generally preferable and the intent
of treatment is largely palliative.
Indications for Postoperative Radiotherapy
Adjuvant radiotherapy to the primary tumor bed, nodal basin,
or both, has been studied as a means of reducing locoregional
recurrence. If adequate margins are obtained, local recurrence
for primary melanoma is infrequent, with rates consistently
reported to be less than 5%.27,28 However, there is a smaller sub-
set of patients with higher rates of failure in the tumor bed,
including deeply invasive T4 disease, the presence of satellitosis,
the presence of desmoplastic subtype, or persistently positive
margins despite multiple attempts at excision. In these cases,
adjuvant RT to the primary tumor bed should be considered
(Fig. 7.15 and Fig. 7.16).
O’Brien and colleagues analyzed 629 patients with head and
neck melanoma and found that increased local recurrence rates
were associated with increased tumor thickness: <0.76 mm, 2%;
0.76 to 1.49 mm, 5%; 1.5 to 3.99 mm, 15%; and ≥4 mm, 20%.29
Typically, adjuvant RT is considered for T4 tumors, although
typically reserved for those with additional high-risk features.
One of which is satellitosis, which represents discontiguous
sites of disease within 2 cm of the primary tumor and is known
to be a marker of increased recurrence risk.30 Desmoplastic
melanoma is a rare histologic subtype (1% of all melanomas)
and is characterized by spindle-shaped cells with associated
collagen production. This subtype is often associated with peri-
neural spread and local recurrence rates have been reported as
high as 20 to 50%.31,32 In these cases, based on the relatively
higher risk for local recurrence, adjuvant RT should be
considered.
More extensive literature guides the use of adjuvant RT to
nodal basins, both in the elective setting and following lymph
node dissection.33,34 Data supporting the benefit of RT in reduc-
ing regional recurrence come from the randomized phase III
study by Burmeister et al in which higher risk patients were
randomized to surgery and lymph node dissection with or
without adjuvant radiation to the nodal basin.35
Eligible
patients had one of the following features associated with
increased failure rates:
1. Serum lactate dehydrogenase <1.5 times the upper limit of
normal and the presence of extracapsular extension (ECE).
2. ≥1 involved parotid node of any size.
3. ≥2 involved cervical nodes and/or ≥3 cm of tumor within a
node.
4. ≥2 involved axillary nodes and/or ≥4 cm of tumor within a
node.
5. ≥3 involved inguinal nodes and/or ≥4 cm of tumor within a
node, and/or recurrent disease.27,30
Importantly, no systemic therapy was delivered in this trial. In
the 217 patients included on the study, those who received RT
were significantly less likely to experience regional recurrence
compared to those in the observation arm (18 vs. 33%;
p =0.041). As distant metastasis is the predominant mode of
melanoma disease failure, it was not surprising that an
improved rate of regional control did not translate into an over-
all survival average (54 vs. 44%; p =0.12). The most common
Grade 3 or 4 adverse events were seroma and wound infections,
which were equivalent in both arms.35 The lack of systemic
therapy in this study as well as the lack of a survival di erence
Fig. 7.15 A 72-year-old man with pT3N2cMx melanoma of the scalp with ulceration and satellitosis treated with wide local excision, free flap
reconstruction, ipsilateral neck dissection, and adjuvant RT to the primary tumor bed. (a) Postoperative image. (b) Axial radiation planning CT slice
demonstrating bolus material (red arrow) for achieving adequate surface dose.
Role of Radiotherapy in the Treatment of Skin Malignancies
141

with the use of RT has raised the question of the true benefit of
adjuvant RT for all patients eligible for this study. That said, it
reinforces the guiding principle where locoregional control is a
priority, and in a case with extensive nodal disease, especially
with extranodal extension and significant soft-tissue involve-
ment, adjuvant RT should be considered as a proven way to
reduce rates of locoregional recurrence ( Fig. 7.17, Fig. 7.18,
and Fig. 7.19).
7.2.3 Dose and Fractionation Paradigms
A crucial radiobiologic principle underlies the choice of dose
and fractionation (the number of treatments chosen to deliver a
given dose) for RT for skin cancers. While higher total doses
typically yield better tumor control, nominal dose is less impor-
tant than the radiobiologic e ective dose. This refers to the fact
that the dose per fraction (fx) also has a highly significant
impact on control rates, as a lower total dose delivered using a
higher daily dose per fraction can yield equivalent oncologic
control rates as higher nominal doses in smaller doses per frac-
tion. For example, while 66 Gy yields higher control rates than
40 to 45 Gy if the daily dose (e.g., 2 Gy) is kept constant, 40 to
45 Gy using 4 to 4.5 Gy per fraction over 10 fractions for 2 weeks
has a fairly similar radiobiologic e ect as does a total dose of
66 Gy using 2 Gy/fx over 33 treatments over 6.5 weeks.
However, the potential drawback of shorter courses of radia-
tion using higher daily doses is that this schedule also delivers
higher doses to normal tissue that overwhelm their repair
capacity, leading to a higher risk of long-term side e ects. As
such, for skin cancer RT, there is a wide array of radiation
schedules that are likely equally e ective. However, shorter reg-
imens using higher daily doses, while o ering superior conven-
ience, may be associated with increased risks of late e ects.36,37
A review of 1,149 irradiated fields for primary NMSC (85.7%)
treated with definitive RT doses ranging from 45 to 80 Gy deter-
mined that hypopigmentation and telangiectases were the
most common cosmetic changes after RT. Ninety days after RT,
hypopigmentation was found in 64.7% of patients, telangiec-
tases in 43.1% of patients, erythema in 24.8% of patients, and
hyperpigmentation in 16.8% of patients. The frequency of cer-
tain cosmetic changes increased with time from RT, with hypo-
pigmentation reported in 91.8% and telangiectases reported in
Fig. 7.16 (a) Coronal planning CTslice for postoperative radiation therapy to the primary tumor bed for scalp melanoma depicted in Fig. 16.15 with
isodose lines covering the target (solid red). (b) Sagittal planning CTslice. (c) Nine-field intensity modulated radiation therapy arrangement (IMRT).
Role of Radiotherapy in the Treatment of Skin Malignancies
142

82.2% of patients 4 years after RT. This relationship was not
observed for keratosis, erythema, and induration.38 Modern
series using either electron beam RT or electronic brachyther-
apy techniques report good to excellent cosmesis in 95 to 100%
of patients, with low rates of long-term dermatitis, alopecia, or
telangiectasias.37 Other patient-related factors, such as the pres-
ence of skin folds within the radiation field, poor nutritional
status, tobacco use, and diabetes can all contribute to increased
risk for radiation-related morbidity.
While cosmetic outcomes may be significantly better with
modern CT-based planning, the fundamental principle of frac-
tionation is still a crucial one when considering the risk of late
e ects. Therefore, for cosmetically sensitive areas, in regions
with adjacent radiosensitive tissue such as cartilaginous, orbi-
tal, and neural structures, and in younger patients with
extended life spans, longer courses of RT using standard daily
doses are preferable. However, for older patients with tumors
that are not associated with cartilaginous, orbital, or neural tis-
sues, or those with transportation or socioeconomic limitations,
and for lesions in cosmetically noncritical locations, lower total
dose RT using higher daily doses over 1 to 3 weeks can be an
extremely attractive option.
As such, there are a wide variety of appropriate radiation
schedules that can be used in the definitive and postoperative
Fig. 7.17 A 40-year-old man with melanoma of the left cheek status treated with wide local excision, superficial parotidectomy, selective lymph node
dissection (levels II–V), and postoperative radiation therapy to the primary tumor bed and ipsilateral cervical lymph nodes. (a) Axial radiation planning
CTslice depicting isodose lines covering target (solid red). The right parotid (orange), oral cavity (yellow), and spinal cord (green) with a safety margin
(green) are spared with the use of IMRT. (b) Coronal radiation planning CTslice depicting ipsilateral nodal coverage by the isodose lines. (c) Nine-field
IMRT beam arrangement.
Role of Radiotherapy in the Treatment of Skin Malignancies
143

settings. However, careful consideration should be given to
the tum or size, location, proxim ity to critical structures,
and importance of cosm esis before choosing appropriate
dose and fractionation schem es. Table 7.1 and Table 7.2
provide representative schedules for the definitive and
postoperative settings, respectively. When elective nodes
are being targeted, typically 45 to 50 Gy in 1.8 to 2.0 Gy per
fraction is appropriate, especially for the groin and axilla,
w hile 54 to 60 Gy in 1.8 to 2.0 Gy per fraction is typically
recom m ended for the head and neck region. Areas with
positive m argins and/or extracapsular extension typically
dem and a focal boost of an additional 6 to 10 Gy, for a total
dose of 66 to 70 Gy, to try and achieve durable locoregional
control.2
Fig. 7.18 A dose volume histogram illustrating
representative normal organs at risk being spared
using IMRT for the radiation treatment plan
depicted in Fig. 17.17. The doses received by
each of these structures are well below their
tolerance.
Fig. 7.19 (a) Digitally reconstructed radiograph depicting a left axillary radiation field for adjuvant radiation to the axilla for a patient with dermal
melanoma. (b) Coronal CT image depicting the left axillary radiation treatment field.
Role of Radiotherapy in the Treatment of Skin Malignancies
144

In addition to producing di erential late e ects, there is
some data that hypofractionated (higher daily dose in less
treatment) regim ens are associated w ith superior tum or
control rates in definitive RT for BCC and SCC. In a retro-
spective review of 531 BCC and SCC treated with definitive
RT, patients with BCC who received ≤2 Gy per fraction had
significantly lower local control com pared w ith patients
w ho received > 2 Gy per fraction (75 vs. 95.9%; p = 0.01). This
was not the case in the SCC cohort.39 However, other studies
have shown conflicting data. In a retrospective review of
434 BCC and SCC, patients treated with 54 Gy in 18 fractions
and 44 Gy in 10 fractions had similar 3-year local recur-
rence-free rate for BCC (97.6 vs. 96.9%) and SCC (97 vs.
93.6%).8 In our experience, there is little rationale for a daily
dose of < 2 Gy, as this unduly extends the treatm ent course
for the patient. Excellent control can be achieved using
shorter or longer courses w ith varying total dose prescrip-
tions. The choice of dose and fractionation is prim arily
driven by proxim ity to norm al tissues, long-term cosm etic
impact, and patient tolerance and convenience factors.
The choice of total dose and dose per fraction in radiation
for cutaneous m elanom a is of particular relevance, given
that this disease dem onstrates radio-resistant properties in
vitro. Num erous cell culture studies have dem onstrated a
broader shoulder on the dose–response curve, requiring and
theoretically suggesting that higher doses per fraction
would be required to achieve e cient tum or cell kill, espe-
cially in the presence of gross disease. A phase III Radiother-
apy Therapy Oncology Group (RTOG) study investigated this
question in the palliative setting by random izing 137
patients with m etastatic m elanom a at any site other than
the brain or abdom en to receive either 32 Gy in 4 fractions
(8 Gy/fx) compared to 45 Gy in 20 fractions (4.5 Gy/fx).
Despite the preclinical data suggesting that there would be
a di erence, the study failed to detect any di erence in clin-
ical response rate between the two arm s.40 However, this
study failed to control for tum ors of w idely varying sizes,
which m ay have reduced the ability to di erentiate between
the arm s.
In the definitive setting, a common radiation schedule is to
deliver 30 to 40 Gy in five to eight fractions. However, if the
intended treatment area is adjacent to critical neural structures,
standard fractionation over several weeks is advised41
(Table 7.3). Control rates for gross unresected melanoma are
suboptimal.
In the postoperative setting, locoregional control rates are
quite good, ranging from 80 to 90%. A few alternative regimens
appear equally e ective. In the study by Burmeister et al, 48 Gy
in 20 fractions was used safely and e ectively.35 Ballo et al pub-
lished the longstanding MD Anderson’s approach which utilized
30 Gy in five fractions given twice weekly, for all sites not adja-
cent to critical neural organs at risk. In these cases, traditional
doses of 60 to 66 Gy in 30 to 33 fx (2 Gy/fx) are typically used.42
7.2.4 Radiation Techniques and
Targeting
The primary goal of radiotherapy is to precisely deliver a maxi-
mum dose of radiation, to a defined tumor volume, that eradi-
cates disease and results in minimal damage to surrounding,
normal tissue. This can be accomplished in a variety of ways,
generally broken up into two categories: (1) external beam
radiation using electrons or photons and (2) internal radiation
known as brachytherapy, using radioactive sources. A lack of
understanding of these di erences has caused an under-appre-
ciation of the distinct modes of treatment available to patients,
and may very well have contributed to excessive treatment fail-
ures and/or poor cosmetic results in some older published ser-
ies in which suboptimal techniques were used.
Table 7.1 Dose and fractionation paradigms for definitive radiation ther-
apy of nonmelanomatous skin cancer
Gross primary tumor

Dose and fractionation regimen
70 Gy in 35 fractions over 7 wk
66 Gy in 30 fractions over 6 wk
55 Gy in 20 fractions over 4 wk
50 Gy in 15 fractions over 3 wk
40 Gy in 5 fractions twice weekly
30 Gy in 3 fractions once weekly
20 Gy in single fraction
Regional nodes
● LN clinically (-), at risk for sub-
clinical disease
● LN clinically (+); Head and Neck
● LN clinically (+); axilla, groin
Dose and fractionation regimen
50–54 Gy over 5–6 wk
50 Gy over 4 wk
Surgical resection preferred
70 Gy in 35 fractions over 7 wk
66 Gy in 30 fractions over 6 wk
55 Gy in 20 fractions over 4 wk
Surgical resection preferred
60–66 Gy in 6 wk
Table 7.2 Dose and fractionation paradigms for postoperative radiation
therapy of nonmelanomatous skin cancer
Primary tumor bed
● Margin negative
● Margin positive
Dose and fractionation regimen
60 Gy in 30 fractions over 6 wk
50 Gy in 25 fractions over 5 wk
50 Gy in 20 fractions over 4 wk
66 Gy in 33 fractions over 6.5 wk
55 Gy in 20 fractions over 4 wk
Regional nodal bed
● Head and neck
○ Without ECE
○ With ECE
● Axilla or groin
○ Without ECE
○ With ECE
Dose and fractionation regimen
60 Gy in 30 fractions over 6 wk
50 Gy in 20 fractions over 4 wk
66 Gy in 33 fractions over 6.5 wk
55 Gy in 20 fractions over 4 wk
45–50 Gy in 25 fractions over 5 wk
60–66 Gy in 30–33 fractions over 6 wk
Table 7.3 Dose and fractionation paradigms for postoperative radiation
therapy of melanoma
Primary tumor/Nodal bed
● Adjacent to critical neural
structures
● Not adjacent to critical neural
structures
Dose and fractionation regimen
60–66 Gy in 30–33 fractions over
6.5 wk
48 Gy in 20 fractions over 4 wk
30 Gy in 5 fractions twice weekly
Role of Radiotherapy in the Treatment of Skin Malignancies
145

External Beam Radiotherapy
Technologic advances over the second half of the 20th century
have produced an evolution in the types of machines that deliver
external radiation used to treat skin cancers. Contact radiation
therapy can be accomplished using a Grenz ray machine which
produces low energy X-rays that operate with beam energies of
10 to 50 kilovolt Peak (kVp). Grenz rays have very low penetra-
tion and are absorbed within the first 2 mm of skin. Given its
superficial penetration, Grenz ray therapy is largely reserved for
in situ malignancies, such as Bowen’s disease, actinic keratosis,
and lentigo maligna, and was also historically used for inflam-
matory processes, such as psoriasis and chronic eczema. While
Grenz ray therapy can be used for the management of very
superficial BCC and SCC, a high index of suspicion to rule out
deeper infiltration is critical. Published treatment regimens with
satisfactory outcomes include 6 Gy twice weekly for 12 fractions,
30 Gy in 1 fraction, 15 Gy every other day for 3 fractions, or
20 Gy every other day for 3 fractions. A cumulative dose of
100 Gy should not be exceeded. The advantage of Grenz ray
therapy is fewer long-term side e ects such as hypo- or hyper-
pigmentation, no alopecia after treatment, and a negligible risk
of secondary RT-induced malignancy.37
Superficial X-rays have been used to treat slightly larger/deeper
lesions with beam energies of 50 to 100 kVp). The larger or deeper
the lesion, the higher the energy that is needed to dose the target.
A customized lead shield is often placed over the skin surface with
a central cutout to collimate, or accurately shape, the beam
(Fig. 7.20). With superficial X-rays, the maximum dose is depos-
ited onto the skin surface, the scatter to surrounding normal tis-
sue is fairly minimal, and the dose distribution is unlikely to be
impacted by irregular or curved surfaces such as found on the
nose, canthus, lip, and external ear. Therefore, superficial is an
ideal treatment for some of the cosmetically sensitive areas where
surgery may not be desirable to the patient. However, X-rays in
this energy range are di erentially absorbed in denser material
like bone or cartilage, and therefore could carry an increased risk
of osteo- or chondronecrosis if the fractionation schedule is overly
aggressive. It should also be noted that orthovoltage is truly
restricted to superficial lesions. At this range of photon energies,
the coverage of the target tissue is very poor beyond several milli-
meters into tissue. In the past, the radiation exposure would be
increased to drive more dose to the desired depth, which created
significant hot spots, resulting in a surface dose 20 to 50% higher
than the planned prescription dose, which may well have led to
poorer cosmetic outcomes. This also may partially account for
inferior outcomes in larger/deeper lesions treated with this tech-
nique, given the coverage at depth may have been suboptimal.37
These issues are avoided with a proper understanding of the tech-
nology and its unique qualities which can make it ideal for super-
ficial skin cancer treatment.
Orthovoltage units and Cobalt units produce higher energy
X-rays and were also commonly used in the past. However, all
of these modalities have largely fallen into disuse and been
replaced by electron and photon therapy produced by linear
accelerators. Electron beam therapy has the advantage of hav-
ing rapid dose fall o at depth, akin to some of the lower energy
X-rays, but can also achieve deeper penetration in tissue
(Fig. 7.21). Electron energy ranges are quite broad, ranging
Fig. 7.20 Superficial radiation machine with customized lead shield for
treatment of nasal skin SCC.
Fig. 7.21 Electron energies. The depth dose profiles for different
electron energies (dose on x-axis and depth on y-axis) is depicted. As
electron energy increases, the maximum dose is deposited deeper in
tissue with higher exit doses. Lower energy electrons are ideal to spare
underlying normal tissue.
Role of Radiotherapy in the Treatment of Skin Malignancies
146

from 6 Megaelectron volts (MeV) up to 21 MeV in clinical prac-
tice, and the higher energy beams can cover targets at depths
up to 4 to 5 cm. Electrons are especially useful for skin cancer,
given the surface dose is quite high and can be augmented to
achieve 100% of the prescription dose with the use of custom-
ized bolus material. En face electrons work best on flat surfaces
that provide homogeneous and predictable dose distributions.
Surfaces with significant concavity can be treated, but often
multiple matching fields are required which introduce addi-
tional planning complexity and the possibility of hot spots at
the match line.
Photons have energy ranges that are nominally sim ilar to
electrons (6–18 Megavolts), but they are typically skin spar-
ing, with entrance doses at the skin of only 15 to 35% of
prescription dose at depth in tissue ( Fig. 7.22). However,
photons are useful when treating targets with complex slop-
ing or concave shapes, and they are the m ost appropriate
m odality for treating deeper tissues such as lymphatic beds,
or nerve pathways. Skin dose can be augmented by using
m ultiple tangential fields, and with the addition of custom -
ized bolus m aterial. For m ore complex plans for deep-seated
tum ors, the advent of intensity m odulated radiotherapy
(IMRT) has been a huge advance in treatm ent planning
capability. By using m ultiple beam angles and allowing for
beam m odulation and consequent di erential radiation
deposition in complex shapes in tissues, high doses are able
to be delivered to very complex targets with rapid dose
fallo and superior sparing of norm al tissue. This has partic-
ular importance when treating the neck and skull base,
given avoidance of salivary glands, swallowing organs, bone,
orbits, optic nerves, and brainstem is routinely achievable.
This technologic advance, coupled with daily im age guidance
using cone beam CT to reduce daily setup error, has been
associated with significant decreases in radiation-induced
m orbidity and has provided greater opportunities to treat
large infiltrative tum ors adjacent to critical organs, or those
tracking into the skull base, w ith greater success.37
Brachytherapy
Brachytherapy involves the placement of a radioactive source
on a body surface (surface-mold technique) or the placement of
a radioactive source into a body tissue (interstitial technique). It
has particular application to lesions of the lip, eyelid, or pre/
post-auricular skin given their irregular contour and proximity
to critical structures. Brachytherapy can achieve very steep dose
fallo to avoid organs at risk that are only several millimeters
away. Brachytherapy is predominantly used in the definitive
setting, but can also be used postoperatively, in the setting of a
positive margin.
Fig. 7.22 Photon beam dose profile for 6-MV
photons. Different field sizes are shown on the
left. Note that the dose falloff is more gradual
compared to electrons (shown in Fig. 7.20).
Role of Radiotherapy in the Treatment of Skin Malignancies
147

Brachytherapy can be accomplished using interstitial
implants or surface mold techniques (Fig. 7.23). Interstitial
brachytherapy involves placing radioactive wires or seeds
directly into the target tissue. Interstitial implants may be per-
manent or temporary. It can be accomplished using low-dose
rate (LDR) over 48 to 72 hours, or high-dose rate (HDR) delivery
using multiple fractions delivered over 5 to 15 minutes. The lat-
ter is far more commonly used currently due to the much wider
availability of HDR delivery units in the radiation oncology
community. In a review of 147 BCC and SCC of the eyelid, can-
thus, nose, or external ear, patients were treated with intersti-
tial wire implant brachytherapy with 192Ir for primary tumors
or recurrent tumors after surgery. The locoregional recurrence
rate at 5 years was 12.7% and was well tolerated. Mild to mod-
erate hypopigmentation, skin atrophy, telangiectasias, and eye-
lid dysfunction were observed, without severe toxicities. No
severe toxicities were observed. As expected, outcomes were
worse for patients with recurrent disease.43
Surface mold brachytherapy is an alternative technique that
is particularly useful in superficial lesions with limited tissue
penetration at depth (1 cm). It involves the placement of a mold
constructed from pliable materials which later harden into a
customized cast-like material onto the target region. The mold
is impregnated with catheters through which radioactive sour-
ces can be precisely directed for discreet time periods, allowing
for precise dose deposition to tumors. The radiation is typically
delivered using a HDR afterloader device, typically with 192Ir.
This technique is particularly advantageous for tumors of the
nasal tip or ala, in which the sloping surface can interfere with
homogeneous dose distributions with electrons or photons
(Fig. 7.24). Mold brachytherapy allows for the customized
Fig. 7.23 (a) High dose rate brachytherapy
machine. (b) Surface mold brachytherapy device
using catheters fashioned on a wax bolus material
to provide adequate surface dose and photon
energy buildup (catheter—black arrow; gel bolus
material—red arrow).
Fig. 7.24 A 94-year-old woman, medically inoperable, with SCC of the
nasal tip treated with external beam radiation therapy with electrons.
Pictured is a 2 × 1.8 cm recurrent SCC, T1N0M0, which was treated
with surface-mold brachytherapy.
Role of Radiotherapy in the Treatment of Skin Malignancies
148

bending of the wax to conform to the complex nasal contour of
the patients and ensures homogeneous dose delivery to the tar-
get (Fig. 7.25).44 HDR surface-mold brachytherapy for treat-
ment of NMSC has been studied in both prospective and
retrospective studies and shown to be safe and e ective. In a
prospective series of 136 patients with BCC and SCC of the face
treated with HDR brachytherapy via external surface mold, a 5-
year local control rate of 99% for primary tumors and 87% for
recurrent tumors was observed. Good or excellent cosmesis
was reported in 98% of patients 6 months after treatment.45
7.2.5 Considerations in
Immunosuppressed Patients with NMSC
Chronic immune suppression is associated with a higher inci-
dence of cutaneous SCC and BCC. This increased risk has been
observed in solid organ transplant recipients (OTRs) on chronic
immunosuppressive therapy, patients with chronic lymphocytic
leukemia (CLL), and exposure to chronic corticosteroid therapy.
OTRs demonstrate up to a 65- to 100-fold increase in incidence
of SCC compared to the immunocompetent population.11 Once
immunosuppressed patients develop a skin cancer, more than
75% will develop additional lesions within 5 years, often within
months of each other.46 In addition to being at increased risk
for malignancy, the chronically immunosuppressed population
more often develop SCC with high-risk features, including PNI,
LVSI, tumors located on the head and neck, nodal metastasis,
and deep tissue involvement. SCC in these patients may demon-
strate more aggressive behavior with poorer outcomes. Skin
cancer in these patients may even account for 5 to 10% of mor-
tality.47 As modern immunosuppressive therapy has become
more potent and e cacious, posttransplant survival time and
duration of immunosuppressive therapy has increased, which
has led to an increase in the incidence of SCC in these patients.
Therefore, aggressive management of these patients is of
increasing importance.
Postoperative RT is recommended for high-risk SCC and plays
an important role in the management of this patient popula-
tion. Whether disease control rates and tolerance of RT di er
according to immune status has not been well defined; how-
ever, available literature suggests that even with postoperative
RT, immunosuppressed patients have worse outcomes than
immunocompetent patients.48 Manyam et al recently reported
a retrospective comparison of 38 immunocompetent and
21 immunosuppressed patients treated for cutaneous SCC of
the head and neck with resection and adjuvant RT. Most had
nodal metastases (63%), 50% had PNI, and 15% were T3/4.
Actuarial locoregional control (48 vs. 73%; p =0.01) and disease-
free survival (44 vs. 62%; p =0.03) at 2 years were significantly
inferior in the immunosuppressed population.49 Immunosup-
pressed patients may be intrinsically more resistant to tradi-
tional adjuvant therapy. Whether these patients may benefit
from intensification of therapy with earlier disposition to RT,
dose-escalated RT, or concurrent systemic therapies requires
future prospective study. SCC in immunosuppressed patients
may also have a higher tendency toward discontinuous pattern
of spread or satellitosis and recurrences can occur further away
from the primary tumor. Therefore, the extent of surrounding
tissue that must be involved in the RT field should be a consid-
eration, especially in the setting of extensive PNI or LVSI.50 Ulti-
mately, evaluation of a chronically immunosuppressed patient
with SCC should warrant a higher degree of caution, even in
early-stage lesions.
Immunosuppressive regimens in this patient population are
also an important consideration. OTRs are typically treated with
calcineurin inhibitors, such as FK-506 and tacrolimus, for pre-
vention of graft rejection; however, these agents have been
shown to be promitotic and contribute to tumor development.
On the other hand, mammalian target of rapamycin (mTOR)
inhibitors, such as sirolimus, have been shown to have antineo-
plastic properties. A phase III randomized controlled trial
involving renal transplant patients demonstrated that use of
sirolimus resulted in significantly decreased incidence of new
SCC (22 vs. 39%; p =0.02) and introduced a significant delay in
Fig. 7.25 Brachytherapy plan for SCC of the nasal
tip depicted in Fig. 7.22. (a) Axial radiation
planning CT scan slice of the mold implant. (b)
Five catheters (red arrow) are incorporated in the
plan. The catheters are resting on a layer of red
bees wax bolus, not seen here. (c) Sagittal
radiation planning CTscan slice with isodose lines
covering the lesion. (d) Dose volume parameters
for the target and normal organs at risk. The
prescription dose was 8 Gy in five fractions.
Role of Radiotherapy in the Treatment of Skin Malignancies
149

the development of new SCC (15 vs. 7 months; p =0.02) com-
pared to patients receiving calcineurin inhibitors. There were
no significantly increased episodes of graft rejection with siroli-
mus, but there were significantly more side e ects.51 Therefore,
the risks and benefits of transitioning to an mTOR inhibitor
after a new diagnosis of SCC in this patient population should
be discussed with the patient and their transplant physician.
7.2.6 Consideration of Concurrent
Systemic Therapy with Radiotherapy
The risk of distant metastasis is extremely low for BCC; there-
fore, the role of systemic therapy has not been extensively
studied. Vismodegib, a small molecule inhibitor of the hedge-
hog pathway, is the first approved systemic therapy for
advanced BCC. The drug is indicated for recurrent or metastatic
BCC that is not amenable to definitive surgery or RT. In a phase
II study of vismodegib, patients with inoperable locally
advanced BCC demonstrated a 43% response rate to the drug
(95% CI: 31–56; p <0.0001) and patients with metastatic BCC
demonstrated a 30% response rate to the drug (95% CI: 16–48;
p =0.001), with serious adverse event rate of 25%. There are no
data currently available regarding its e cacy as a concurrent
therapy with postoperative or definitive RT, though clinical tri-
als are underway to explore this application.52
The overall risk of distant metastasis with SCC is also
extremely low, about 3.7%. Currently, there are no prospective
phase III trials to evaluate the benefit of the addition of concur-
rent systemic therapy to definitive or postoperative RT for high-
risk SCC. Much of the decision to include systemic therapy has
been extrapolated from phase III randomized trials conducted
in head and neck mucosal SCC treated with postoperative RT
and concurrent platinum-based chemotherapy. These trials
demonstrated significantly higher locoregional control and pro-
gression-free survival with concurrent postoperative RT and
cisplatin compared to postoperative RT alone, though there
were significantly higher rates of severe adverse e ects.53,54
Further analysis of these trials demonstrated that positive mar-
gins and lymph node extracapsular extension were the two risk
factors for which concurrent chemotherapy was beneficial.22
Patients with cutaneous SCC with these risk factors should con-
sider multidisciplinary consultation to discuss supplementation
of RTwith cisplatinum-based chemotherapy.
Epidermal grow th factor receptor (EGFR) inhibitors have
been a source of interest as m onotherapy or in combination
with surgery and/or RT for cutaneous SCC. A phase II study
investigated the use of neoadjuvant gefitinib followed by
surgery, RT, or both in 22 patients w ith locally advanced
cutaneous SCC. A complete response rate was observed in
18% of patients, a partial response rate was observed in 27%
of patients, and a 2-year progression-free survival of 60%
was observed.55 Similarly, another EGFR inhibitor, cetuxi-
m ab, used as a monotherapy dem onstrated a 30% response
rate and 70% disease stabilization rate in a phase II trial in
patients with unresectable or metastatic cutaneous SCC.56
However, there is an absence of data investigating the added
utility of EGFR inhibition, given concurrent with radiation in
either the definitive or adjuvant settings.57,58
In our practices, we consider the addition of concurrent cis-
platin to adjuvant radiotherapy for patients with extranodal ex-
tension of disease and those with positive margins, and in
conjunction with definitive RT for patients with unresectable
disease (e.g., skull base invasion). For patients who are not can-
didates for cisplatin, either due to age and/or renal function
concerns, we also consider concurrent cetuximab.
7.2.7 Palliative Radiotherapy for
Metastatic Disease
Traditional principles of palliative radiotherapy apply to skin
cancers of all varieties. Palliation is typically o ered for focal
symptomatic areas, such as pain, bleeding, and airway compres-
sion. Radiation therapy is also indicated in asymptomatic
patients when metastases threaten to cause significant morbid-
ity in the near future. This would include femoral lesions at risk
of fracture, spinal lesions with epidural extension which can
cause spinal cord compression, and brain metastases which can
cause neurological morbidity and mortality when progressive.
Typical palliative fractionation schemes include 30 Gy in 10
Role of Radiotherapy in the Treatment of Skin Malignancies
150

fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in 1
fraction ( Fig. 7.26).59
Advanced radiation technologies using high-dose single-frac-
tion stereotactic radiosurgery (SRS) or single or multifraction
stereotactic body radiotherapy (SBRT) have an important role
to play in several circumstances of metastatic disease. Brain
metastases are a significant problem in malignant melanoma
and account for 20 to 54% of deaths in these patients
(Fig. 7.27).60 SRS, either through gamma knife radiosurgery,
or linear accelerator-based radiosurgery, has been shown to be
quite e ective in the treatment of these lesions when the size
of the metastasis remains small enough to be amenable to these
approaches ( Fig. 7.28, Fig. 7.29, and Fig. 7.30).61,62,63 Mori
and colleagues analyzed 60 patients with metastatic melanoma
to the brain treated with SRS (mean dose: 16.4 Gy) and found
imaging-defined local control rate of 90%, with complete disap-
pearance in 11% of patients.61 Similarly, spine radiosurgery for
spinal metastases has been reported to produce high rates of
pain control and radiographic local control in melanoma
patients, with minimal side e ects ( Fig. 7.31). SBRT has also
been shown to be highly e ective and safe for patients with oli-
gometastatic lung or liver metastases.
Fig. 7.27 Axial T1 contrast-enhanced MRI images showing multiple brain metastases from dermal melanoma.
Fig. 7.26 (a) Axial radiation planning CTscan slice depicting whole-brain palliative radiation therapy for brain metastases from dermal melanoma with
a prescription dose of 30 Gy in 10 fractions. (b) Whole brain radiation therapy lateral field.
Role of Radiotherapy in the Treatment of Skin Malignancies
151

Fig. 7.29 Gamma knife head frame used for immobilization during
gamma knife radiosurgery.
Fig. 7.28 Gamma knife radiosurgery delivery
system (Perfexion model).
Role of Radiotherapy in the Treatment of Skin Malignancies
152

Fig. 7.30 A 58-year-old man with single brain metastasis from cutaneous melanoma treated with gamma knife radiosurgery to 24 Gy in one fraction. (Top
panels—left to right: axial, coronal and sagittal MRI images depicting the lesion and 24 Gy isodose in light green; Bottom panel—corresponding CT images)
Fig. 7.31 (a) Axial slice of a radiation planning CT
demonstrating delineation of a T8 vertebra
metastasis from cutaneous melanoma treated
with a single session of spine SBRT to 16 Gy in
one fraction (target in green, spinal cord in pink,
16 Gy isodose line in yellow). (b) A seven-field
IMRT beam arrangement for the lesion (target
depicted in green and cord shown in pink).
Role of Radiotherapy in the Treatment of Skin Malignancies
153

For recurrent NMSC, often locoregional recurrence presents
the greatest therapeutic challenge and is a primary cause of
morbidity and mortality in the small number of patients who
do not achieve cure. As this often occurs in the head and
neck region, head and neck SBRT is an emerging therapeutic
option to achieve durable locoregional salvage ( Fig. 7.32,
Fig. 7.33, and Fig. 7.34).64 After a phase I study demon-
strated the safety of using up to 44 Gy in five fractions for
recurrent, previously radiated head and neck SCCs, hundreds
of patients were treated with this approach. Response rates
were high at 50 to 75%, and morbidity was uniformly modest
with grade 3/4 toxicity rates between 10 and 15% when
delivered in an every-other-day regimen. Although the use of
this regimen in skin cancer seems quite logical, one must
extrapolate as the data apply only to mucosally based head
and neck cancers at present.
7.2.8 Radiotherapy and
Hyperthermia for Melanoma
For large, unresectable, often recurrent skin cancers being
treated with radiotherapy, concurrent hyperthermia, using
temperatures of 40 to 45°C, has been shown to o er a
significant radiosensitization e ect and direct cytotoxic e ect,
as it selectively damages cells in the S phase of mitosis, a time
in the cell cycle that radiotherapy is particularly ine ective.65,66
A study of metastatic or recurrent melanoma was conducted
by the European Society of Hyperthermic Oncology in which
70 patients were randomized to RT with or without hyperther-
mia. Patients who received hyperthermia with RT (24–27 Gy in
three fractions) had a significantly higher 2-year local control
rate compared to patients who received RT alone (46 vs. 28%;
p =0.008). There was no significant di erence in survival
between the two groups.67 This also is an important potential
adjunct to radiotherapy for large unresectable skin cancers. In
our experience, hyperthermia can be particularly useful as an
adjunctive concurrent treatment to be used with RT in patients
who have had prior radiation therapy to the area. With the use
of hyperthermia, the e cacy of the radiation therapy increases,
and thus the total doses of RT can be lower, which is advanta-
geous for a scenario of reirradiation.
7.2.9 Conflict of Interest
Dr. Yom receives clinical trial support from Genentech, Inc.
Fig. 7.32 A 58-year-old man with history of chronic immunosuppres-
sion, with recurrent, fungating scalp SCC treated with surgery and two
courses of palliative stereotactic body radiotherapy.
Fig. 7.33 Stereotactic body radiation therapy. (a) Axial radiation
planning CTslice depicting the prone set up with soft-tissue extension
through the skull (red arrow) and overlying bolus (blue arrow).
(b) Isodose lines covering the target (solid purple) with a prescription
of 30 Gy in five fractions.
Role of Radiotherapy in the Treatment of Skin Malignancies
154

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[57] Kim S, Ele M, Nicolaou N. Cetuximab as primary treatment for cutaneous
squamous cell carcinoma to the neck. Head Neck. 2011; 33(2):286–288
[58] Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as
first-line single-drug therapy in patients with unresectable squamous cell
carcinoma of the skin. J Clin Oncol. 2011; 29(25):3419–3426
[59] Lutz ST, Lo SS, Chang EL, et al. Expert Panel On Radiation Oncology-Bone
Metastases. ACR Appropriateness Criteria® non-spine bone metastases. J Pall-
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[60] Skibber JM, Soong SJ, Austin L, Balch CM, Sawaya RE. Cranial irradiation after
surgical excision of brain metastases in melanoma patients. Ann Surg Oncol.
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[61] Mori Y, Kobayashi T, Shibamoto Y. Stereotactic radiosurgery for metastatic
tumors in the pituitary gland and the cavernous sinus. J Neurosurg. 2006;
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[62] Yu C, Chen JC, Apuzzo ML, et al. Metastatic melanoma to the brain: prognostic
factors after gamma knife radiosurgery. Int J Radiat Oncol Biol Phys. 2002; 52
(5):1277–1287
[63] Selek U, Chang EL, Hassenbusch SJ, III, et al. Stereotactic radiosurgical treat-
ment in 103 patients for 153 cerebral melanoma metastases. Int J Radiat
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[64] Lim CM, Clump DA, Heron DE, Ferris RL. Stereotactic Body Radiotherapy
(SBRT) for primary and recurrent head and neck tumors. Oral Oncol. 2013;
49(5):401–406
[65] van der Zee J. Heating the patient: a promising approach? Ann Oncol. 2002;
13(8):1173–1184
[66] Kroon BB, Bergman W, Coebergh JW, Ruiter DJ, Dutch Melanoma Working
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[67] Overgaard J, Gonzalez Gonzalez D, Hulshof MC, et al. Hyperthermia as an
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Role of Radiotherapy in the Treatment of Skin Malignancies
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8 Surgical Implications of Systemic Therapy for Skin Cancer
Vadim P. Koshenkov, Oliver Eng, and Howard L. Kaufman
8.1 Introduction
Skin cancer is the most common form of cancer worldwide.
Basal cell and squamous cell carcinomas represent the vast
majority of these cancers and are associated with sun and ultra-
violet radiation exposure. In the United States, it is estimated
that 3.5 million nonmelanoma skin cancers are diagnosed
annually, with 20% being squamous cell carcinoma.1 While mel-
anoma is far less frequent with 87,110 new cases expected in
2017, it accounts for at least 50% of mortality from all skin can-
cers. The incidence of melanoma has been steadily increasing
by approximately 2.6% annually since the 1970s.2 Skin cancer
mortality has also been increasing, largely related to the recent
increase in squamous cell carcinoma deaths. In 2017, it is
expected there will be almost 9,730 deaths from melanoma and
up to 8,800 deaths from squamous cell carcinoma.2,3
While the prognosis for most patients diagnosed with skin
cancer is excellent, major challenges exist in treating advanced
squamous cell carcinoma and metastatic melanoma. Approxi-
mately 5% of all patients with squamous cell carcinoma (nearly
30,000 patients annually) have high-risk tumors with signifi-
cant rates of regional and distant metastases.4 Most of the
8,791 deaths attributable to squamous cell carcinoma occur in
these patients. Similarly, while 5-year survival rates for early-
stage melanoma approach 98%, the overall survival for stage IV
disease remains less than 20%.5 In the past few years, however,
major advances in the treatment of patients with metastatic
melanoma have occurred. The developments in targeted thera-
peutics and tumor immunotherapy have revolutionized the
management of metastatic melanoma. From 2011 to 2015,
there have been seven new U.S. Food and Drug Administration
(FDA)-approved agents. The roles of targeted therapy and
immunotherapy are also being explored in nonmelanoma skin
cancers.
During the 20th century and the first decade of the 21st cen-
tury, only two agents were available for the treatment of meta-
static melanoma. These were dacarbazine, an alkylating agent,
and high-dose interleukin-2 (IL-2), an immunotherapy drug.6
Since 2011, multiple agents have been shown to improve pro-
gression-free and/or overall survival for patients with advanced
melanoma. These include ipilimumab (a first-generation T-cell
checkpoint inhibitor), vemurafenib and dabarafenib (BRAF
inhibitors), and trametinib (a selective MEK inhibitor).7,8,9 Addi-
tionally, dramatic results with newer immunotherapy drugs,
such as programmed death-1 (PD-1) and PD-1 ligand 1 (PD-L1)
inhibitors, have been promising with two PD-1 inhibitors, pem-
brolizumab and nivolumab, being approved in 2014 for second-
line treatment of metastatic melanoma. Several clinical trials
are also under way to evaluate these new agents in the adjuvant
treatment of melanoma and for the treatment of metastatic
skin cancers, including squamous cell carcinoma and Merkel
cell carcinoma. As the list of these agents grows and therapeutic
e cacy improves, the number of people who are living longer
with advanced melanoma is likely to rise. In these patients, the
role of surgery in the treatment of metastatic disease will prob-
ably expand in order to augment the benefits of newer, more
potent systemic therapies. Sim ilarly, the surgeon m ust be
fam iliar with the indications and toxicity profiles of these
agents to m axim ize the benefit of surgical intervention in
this new era of systemic cancer therapy. This chapter will
briefly discuss the new system ic agents and highlight impli-
cations for surgical m anagem ent, focusing on m elanom a and
squam ous cell carcinoma.
8.2 Systemic Therapy of
Melanoma
Treatment options for patients with metastatic melanoma
include cytotoxic chemotherapy, targeted therapy, and immu-
notherapy. Surgical resection and radiotherapy are supplemen-
tary or palliative, and can be beneficial in carefully selected
patients with minimal metastatic disease or isolated residual
disease after systemic therapy. Consensus guidelines from the
Society for Immunotherapy of Cancer (SITC) and the National
Comprehensive Cancer Network (NCCN) are available to help
choose the type and order of therapy for patients with
advanced melanoma10,11
(
physician_gls/PDF/melanoma.pdf). A multidisciplinary team
consisting of medical, surgical radiation oncology, and molecu-
lar pathology and radiology is pivotal in providing appropriate
treatment of such patients. Patients with advanced melanoma
should be evaluated with a serum lactate dehydrogenase level,
for the purposes of staging and monitoring response to treat-
ment as well as whole-body imaging, with particular attention
to visceral organs, central nervous system (CNS), and bone. For
patients with disease that can be completely resected with
negative margins, metastasectomy is indicated and has been
associated with 30 to 35% 5-year survival.10,11 Radiation therapy
has also been useful in patients with large, matted lymph node
disease, especially in the neck and axillary nodal basins. It has
also been beneficial in patients with painful bone lesions and
CNS disease.
8.2.1 Chemotherapy
While cytotoxic chemotherapy is not as e ective for melanoma
as for other cancers, it may still play a role in the management
of the disease. The only chemotherapy agent approved by the
FDA for the treatment of metastatic melanoma is dacarbazine
(DTIC). It has been available since 1974.12 Less than 5% of
patients experience a complete response, and 5-year survival
rates range from 2 to 6%. However, objective response rates can
be as high as 20%, and it is relatively well tolerated.13 DTIC
remains the single-agent chemotherapy drug of choice given
that no high-quality trial has shown a survival benefit with
another chemotherapy drug.
Temozolomide is an oral analog of dacarbazine with the
added advantage of CNS penetrance. In a study that compared
the two agents, there was no di erence in objective response
rate (21% with temozolomide vs. 18% with dacarbazine), overall
survival (7.7 vs. 6.4 months; p =0.20), or side e ect profile.14
Surgical Implications of Systemic Therapy for Skin Cancer
158

Temozolomide can be used in place of dacarbazine in the set-
ting of brain metastases or if oral administration is desired.
Multiple combination chemotherapy regimens have been
studied in attempts to improve on the minimal e cacy of the
above-described monotherapy. A combination of cisplatinum,
vinblastine, and dacarbazine (CVD) has been widely used, but it
has yielded increased toxicity without a survival benefit.15,16 A
combination of carboplatin and paclitaxel in the setting of pro-
gression on dacarbazine or temozolomide has shown promising
results in a phase II clinical trial.17 An objective response rate of
26% and an overall survival of 7.8 months were reported. Bio-
chemotherapy, in which interferon alfa-2b (IFNα2β) and low-
dose IL-2 are added to CVD, has also been tested in attempts to
improve outcomes. However, two large randomized clinical tri-
als have demonstrated an increase in adverse events without
improvement in overall survival when compared to standard
chemotherapy.18,19
8.2.2 Targeted Therapy
BRAFand MEK Inhibitors
Multiple molecular pathways with gene mutations that drive
tumor progression in melanoma cells have been identified,
resulting in the development of molecular inhibitors. BRAF
inhibitors, MEK inhibitors, vascular endothelial growth factor
(VEGF) inhibitors, and CKIT inhibitors are all pertinent to the
discussion of targeted therapy in melanoma. The BRAF pathway
utilizes RAS-RAF-MEK-ERK signaling proteins ( Fig. 8.1). BRAF
mutations lead to constitutive activation of the pathway and
are critical to cell signaling, tumor growth. Activating mutations
in BRAF occur in approximately 50% of cutaneous melanomas.20
Mutations in RAS, BRAF, and MEK proteins lead to continuous
activation of the pathway despite the absence of a growth
ligand. The most common BRAF mutation is at amino acid posi-
tion 600 resulting in an exchange of valine for glutamic acid
(V600E). All patients with advanced melanoma should be tested
for BRAF mutation because of its relatively high prevalence and
potential pharmacologic treatment options.
The first BRAF inhibitor, vemurafenib, was approved by the
FDA in 2011 for use in BRAF-mutated metastatic melanoma.8 In
a phase III clinical trial of 675 treatment-naive patients, vemur-
afenib was compared to dacarbazine, and was associated with
an improvement in progression-free survival (5.3 vs. 1.6
months, p <0.001) and 6-month survival (84 vs. 64%). Tumor
regression was seen in up to 50 to 70% of patients across clinical
trials.8,21,22 Median time to response was short—approximately
4.5 weeks; however, resistance was common, typically within 7
to 8 months after the initiation of therapy. Several strategies,
such as combination therapy and discontinuous dosing, are
being attempted in order to lower the emergence of resistance.
Dabrafenib is another BRAF inhibitor that has also demon-
strated improved progression-free survival compared to dacar-
bazine (5.1 vs. 2.7 months, p <0.001), with an objective
response rate of 52%.23 As a result of this trial, dabrafenib was
approved by the FDA in 2013. Both vemurafenib and dabrafenib
can be taken orally. Both have a slightly higher toxicity profile
than dacarbazine, and dose reduction may be necessary in up
to 38% of patients.8 The adverse events of these agents include
fatigue, arthralgias, myalgias, skin hypersensitivity, and devel-
opment of skin lesions, such as acanthomas and cutaneous
squamous cell carcinoma.
Trametinib, an oral MEK inhibitor that has been FDA-approved
since 2013, was tested against dacarbazine or paclitaxel in a
phase III clinical trial that included 322 patients with BRAF
V600E or V600K mutation metastatic melanoma.24 Progression-
free survival (4.8 vs. 1.5 months, p <0.001) and 6-month survival
(81 vs. 67%, p =0.01) were both superior with trametinib. Objec-
tive response rate was 22%, which was lower than with BRAF
inhibitors, and reported side e ects were fewer. Skin reactions
were common, such as rash, dermatitis, acneiform, dry skin,
pruritus, and paronychia. However, these were generally mild.
Other side e ects included diarrhea, stomatitis, abdominal pain,
lymphedema, hypertension, and hemorrhage.
Fig. 8.1 BRAF pathway and cell signaling.
Surgical Implications of Systemic Therapy for Skin Cancer
159

Mutations in MEK may be responsible for resistance to BRAF
inhibitors. A phase II clinical trial was conducted in which 162
patients were treated with either dabrafenib alone or a combi-
nation of dabrafenib and trametinib.9 Median progression-free
survival was considerably improved with dual therapy from 5.6
to 9.4 months, while the objective response rate was 76 versus
54% (p =0.03). Interestingly, the development of squamous cell
carcinoma, which is seen in about 20% of patients with mono-
therapy BRAF inhibitors, was more than halved by the addition
of the MEK inhibitor. Depending on the dose of trametinib, the
incidence of squamous cell carcinoma ranged from 2 to 7%
(p =0.004 and 0.09). While other skin changes associated with
BRAF inhibitors were less frequent in the combination therapy
group, MEK inhibitor–associated toxicities were common. More
recently, these findings were replicated in the setting of a phase
III clinical trial that included 423 previously untreated
patients.25 In the dual therapy group, there was an improve-
ment in progression-free survival (9.3 vs. 8.8 months, p =0.03),
objective response rate (67 vs. 51%, p =0.002), and 6-month sur-
vival (93 vs. 85%, p =0.02). Similarly, the incidence of squamous
cell carcinoma was lower in the combination therapy group
(2 vs. 9%).
Anti-VEGFand CKIT Inhibitors
VEGF and CKIT represent other possible therapeutic targets for
drug development in melanoma. There has been lack of e cacy
with anti-VEGF agents when used alone, and somewhat disap-
pointing results when used in combination with cytotoxic
chemotherapy.26 In the setting of a phase II clinical trial,
214 patients were treated with carboplatin and paclitaxel with
or without bevacizumab. The di erences in progression-free
survival (5.6 vs. 4.2 months), objective response rate (25.5 vs.
16.4%), and median overall survival (12.3 vs. 9.2 months) all
failed to reach statistical significance.
Imatinib, a CKIT inhibitor, has significantly improved out-
comes in patients with gastrointestinal stromal tumors and
chronic myelogenous leukemia. CKIT mutations are present in
approximately 6% of all melanomas, but higher rates have been
reported in patients with mucosal and subungual lesions.27 A
phase II clinical trial was conducted in which 24 patients with
CKIT-mutated melanoma were treated with imatinib, and an
objective response rate of 29% was reported.28 The disease con-
trol rate was 50%, but varied considerably between CKIT muta-
tions and CKIT amplifications (77 vs. 18%).28 These data suggest
there may be a role for VEGF and CKIT inhibition, but to date,
the results of clinical trials have not been su cient to mandate
clinical approval of these agents. Nonetheless, melanoma
patients may be exposed to these drugs as part of clinical trials.
8.2.3 Immunotherapy
Immunotherapy can be defined as the augmentation of the host
immune system to combat cancer cells. This is possible because
B and T cells can recognize tumor-associated antigens, resulting
in cytotoxicity of tumor cells. This process can initiate a cascade
of immune responses against multiple antigens released by
dying tumor cells leading to the eventual elimination of tumor.
The important role of T cell–mediated immunity has been
widely recognized, leading to the development of several
immunotherapy agents designed to promote activation or pre-
vent inhibition of T cell responses. These include cytokines,
such as interferon and IL-2, and, more recently, inhibitors of T
cell checkpoints, such as ipilimumab, pembrolizumab, and
nivolumab. All five aforementioned agents, as well as a pegy-
lated form of interferon, have been approved by the FDA for the
treatment of metastatic melanoma. In contrast to chemother-
apy and targeted therapy, which are associated with rapid onset
of response with eventual resistance, immunotherapy may have
a more delayed onset of activity without the association with
resistance. It often can also induce durable responses, even in
patients with advanced metastatic disease.
Interleukin-2
IL-2, which was approved by the FDA for metastatic melanoma
treatment in 1998, had been extensively studied for three de-
cades in mouse models as well as human clinical trials. The
exact antitumor mechanism is unclear, but IL-2 appears to
function by promoting large volume expansion of tumor-spe-
cific e ector T cells. Two large trials were integral in testing the
e ectiveness of IL-2. A single-institution clinical trial, which
included 409 patients with either metastatic melanoma
(n =182) or renal cell carcinoma (n =227), demonstrated that
high-dose IL-2 led to an objective response rate of 17.1%, with
8.1% of patients achieving a complete response.29 A subsequent
multi-institutional clinical trial in 270 patients with metastatic
melanoma showed similar results, with an objective response
rate of 16% and a complete response rate of 6%.30 Perhaps, the
most remarkable finding of the trial was the durability of the
responses. In the responder group, the median duration of com-
plete response was 59 months, and 40% of patients were dis-
ease-free for over 70 months.31 Therapy with IL-2 is associated
with considerable morbidity related to capillary leak syndrome.
However, toxicities are usually reversible and guidelines exist to
help clinicians manage these.32
Ipilimumab
Ipilimumab is a monoclonal antibody that targets the T cell
checkpoint inhibitor, cytotoxic T-lymphocyte antigen-4 (CTLA-
4), found on the surface of activated T cells (Fig. 8.2). T cells
are activated through a series of signals, with the first signal
provided by the T cell receptor upon recognition of cognate
antigen presented as processed peptides bound to major histo-
compatibility complexes. The second signal is provided by
CD28, which is also found on the surface of T cells, activating
proliferation and cytokine production upon binding to the co-
stimulatory molecules, B7.1 and B7.2. After activation, CTLA-4
is mobilized to the T cell surface and modulates T cell activity
by binding B7.1 and B7.2 with high a nity and inhibiting T cell
proliferation and cytokine production. Ipilimumab prevents
CTLA-4 from inhibiting T cell activity and hence prevents T cell
inhibition, allowing a more prolonged, and thus potent, T cell
response. In a phase III clinical trial of 676 patients with
advanced melanoma, patients were randomized to ipilimumab
alone, combination with a gp100 peptide vaccine, or both.
There was an improvement in overall survival with ipilimumab
(10 vs. 6 months, p =0.0026) given alone or in combination
compared to vaccine alone.7
Interestingly, there was no
Surgical Implications of Systemic Therapy for Skin Cancer
160

significant di erence in progression-free survival between
treatment arms, suggesting a delayed therapeutic response
with ipilimumab.
Ipilimumab has also been used in combination with dacarba-
zine or granulocyte-macrophage colony-stimulating factor
(GM-CSF) in two large clinical trials.33,34 When used in conjunc-
tion with dacarbazine, 1-year survival was significantly
improved (47.3 vs. 36.3%).33 However, grade 3 or higher adverse
events were more than doubled in the combination group (56.3
vs. 27.5%, p <0.001). When given together with GM-CSF, 1-year
survival was significantly improved over ipilimumab alone
(68.9 vs. 52.9%, p =0.01), but the combination was paradoxically
associated with fewer side e ects.34 Adverse events associated
with ipilimumab include autoimmune dermatitis, colitis, hepa-
titis, hypophysitis, and rarely peripheral neuritis and pancreati-
tis. Early detection is paramount to treatment, as therapy
discontinuation, administration of corticosteroids, and, in rare
cases, infliximab have been shown to be successful in the
management of the autoimmune-related toxicities.35
PD-1 and PD-L1 Inhibitors
The PD-1 receptor is another T cell checkpoint that is expressed
on the surface of T cells after activation (Fig. 8.2). Although
PD-1 expression is observed shortly after T cell activation, it
serves as a marker of T cell exhaustion and functions similarly
to CTLA-4 in downregulating T cell responses. PD-1 signaling is
triggered by binding to one of two ligands, called PD-L1 and
PD-L2.36 Inhibition of PD-1 binding to PD-L1 has been proposed
as another strategy for preventing or reversing T cell
exhaustion, and this has shown significant prom ise in the
treatment of melanom a, non–sm all cell lung cancer, bladder
cancer, Hodgkin’s lymphoma, and other cancers. In 2014,
two PD-1 inhibitors, pem brolizum ab and nivolum ab, were
FDA-approved for the treatm ent of m etastatic m elanoma in
the second-line setting.
In a phase I clinical trial, 135 melanoma patients were treated
with an anti-PD-1 antibody in a dose escalation manner.37 The
objective response rate across all dose cohorts was 38%, with a
rate of 52% at the highest dose. Importantly, prior therapy with
ipilimumab did not appear to impact this e ect. The median
duration of response had not been reached at the time of the
analysis, with a median follow-up time of 11 months, indicating
a very durable response. The PD-1 inhibitor was well tolerated
with few grade 3/4 toxicities. In another clinical phase I trial
that included 52 patients with advanced cancer, an anti-PD-L1
antibody resulted in a 17.3% objective response rate.38 Most of
the responses lasted for longer than 1 year and only 9% of
patients experienced grade 3/4 toxicity.38 More recently, nivo-
lumab, an anti-PD-1 antibody, was compared to dacarbazine in
the setting of a clinical phase III trial of 418 previously
untreated melanoma patients without a BRAF mutation.39 One-
year survival (72.9 vs. 42.1%, p <0.001), progression-free sur-
vival (5.1 vs. 2.2 months, p <0.001), and objective response rate
(40.0 vs. 13.9%, p <0.001) were all superior in nivolumab-
treated patients. PD-L1 expression was present in 35.4% of pre-
treatment tumor samples in the 418 patients, and was associ-
ated with higher response rates in the nivolumab-treated group
(52.7 vs. 33.1%), but not in the dacarbazine group (10.8 vs.
15.7%). Treatment-related grade 3 or higher toxicities were less
frequent in the nivolumab cohort compared to the dacarbazine
group (11.7 vs. 17.6%).
The clinical success of T cell checkpoint inhibitors has led to
an interest in combination regimens. This was tested in a
Fig. 8.2 Various T-cell pathways and sites of
action of immunotherapy agents in melanoma.
Surgical Implications of Systemic Therapy for Skin Cancer
161

clinical phase I trial that included 53 melanoma patients who
underwent concurrent therapy and 33 patients who received
sequential therapy using ipilimumab and nivolumab.40 The
objective response rates were 40 and 20%, respectively. At max-
imal tolerable doses in the concurrent group, the response rate
reached 53%, and 18% of patients underwent a rapid complete
response. The toxicity profile in the concurrent group was no
worse than what has been observed for monotherapy treat-
ment with ipilimumab. A large randomized trial of this combi-
nation in melanoma is in progress.
Oncolytic Virus Immunotherapy
Another approach to imm unotherapy involves directly
infecting cancer cells with native or recombinant oncolytic
viruses. These are viruses that preferentially replicate within
tum or cells, induce lytic tum or cell death, release danger-
associated molecular signals, and prom ote antitum or
im munity by release of tumor-associated antigens in the
context of a viral infection. Numerous vectors have shown
prom ise in therapeutic murine models and early phase clin-
ical trials, including adenovirus, adeno-associated virus, her-
pesvirus, reovirus, vaccinia virus, coxsackievirus, and
Newcastle disease virus. Skin cancers, m ost notably m ela-
noma, have been logical targets for oncolytic virus im muno-
therapy because patients often have accessible lesions for
injection and these tum ors are inherently im m unogenic.
In terms of clinical development, there are considerable data
supporting the use of a modified herpes simplex type I virus
encoding human GM-CSF (termed talimogene laherparepvec or
T-VEC). The T-VEC virus is attenuated by deletion of two patho-
genic viral gene segments, which prevent neurotropism. T-VEC
also encodes GM-CSF, which can help recruit and mature den-
dritic cells to engulf dying tumor cells and initiate a tumor-spe-
cific T cell response. A phase II clinical trial was conducted in 50
patients with advanced or metastatic melanoma with lesions
accessible for direct intratumoral injection.41 An objective res-
ponse rate for both the injected and noninjected disease was
26%, and a mild toxicity profile was observed that included
low-grade constitutional symptoms and injection site reac-
tions.41 One-year and 2-year survival rates were 58 and 52%,
respectively, suggesting a durable response when present.
Patients treated with T-VEC also demonstrated accumulation of
melanoma-specific e ector CD8 +T cells within injected tumors
and a decrease number of suppressive regulatory CD4 +T cells
and myeloid-derived suppressor cells.
T-VEC has also been tested in a phase III clinical trial enrolling
436 patients with advanced melanoma, who were randomized
in a 2:1 fashion to receive T-VEC or recombinant GM-CSF.42 The
objective response rates were 26 and 6% in the two groups,
while the durable response rate, the primary end point of the
trial, was 16 versus 2% (p <0.0001). Median overall survival was
also higher in subjects treated with T-VEC (23.3 vs. 18.9 months,
p = 0.051). Grade 3 or higher adverse events occurred in less
than 3% of patients treated with T-VEC. Combination
approaches using T-VEC and ipilimumab are now being studied
in a clinical phase Ib/II trial with preliminary data demonstrat-
ing an earlier response onset than with ipilimumab alone and
an improvement in the objective response rate.43
8.3 Adjuvant Therapy of
Melanoma
8.3.1 Interferon Alfa-2b
Melanoma patients with metastasis to regional lymph nodes
(stage III) are at high risk for recurrence. High-dose IFNα2β has
been approved by the FDA for the adjuvant therapy of stage III
melanoma since 1996. The exact mechanisms responsible for
the antitumor activity of interferon are incompletely defined
but likely include immunomodulation, direct antiproliferative,
and proapoptotic e ects, possibly through an antiangiogenesis
mechanism. One of the first large clinical trials to investigate
the e cacy of IFNα2β as an adjuvant agent for high-risk mela-
noma enrolled 287 patients who had undergone wide local
excision and lymphadenectomy.44 Both progression-free sur-
vival (20 vs. 12 months) and overall survival (45.6 vs.
33.6 months) were improved with high-dose IFNα2β when
compared to placebo. Toxicities were significant in the
majority of patients and dose modification was frequently
required. The FDA approved interferon based on the results of
this trial. A follow-up study that enrolled 642 patients com-
pared high-dose IFNα2β with low-dose IFNα2β and placebo.45
Progression-free survival, but not overall survival, was superior
in the high-dose IFNα2β group. A subsequent phase III clinical
trial that randomized patients to either induction therapy only
with high-dose IFNα2β or placebo was conducted.46 This trial
was closed prior to completion because preliminary results
showed no di erence in progression-free survival and overall
survival between the two groups.
Pegylated IFNα2β was evaluated as a strategy to optimize
e cacy and limit toxicity because this type of drug formulation
increases absorption and half-life. A phase III clinical trial that
included 1,256 resected node-positive melanoma patients ini-
tially suggested a benefit in progression-free survival, which
was most pronounced in patients with a single positive lymph
node metastasis and in patients with ulcerated primary lesions.
While this resulted in FDA approval, neither progression-free
survival nor overall survival benefit was sustained after long-
term follow-up of 90 months.47 Additionally, the drug had to
be discontinued in 37% of patients because of toxicity. Multiple
meta-analyses have been performed in attempts to determine
whether both progression-free survival and overall survival
are improved with high-dose IFNα2β. Most have shown that
while progression-free survival benefits from this therapy, this
e ect does not extend to overall survival when patients are fol-
lowed up for a prolonged period.48,49,50
8.3.2 Ipilimumab
The limited improvement in outcomes seen with INFα2β in the
adjuvant setting has prompted a search for a better agent. Ipili-
mumab, an immunotherapy drug that has been shown to
improve overall survival in patients with metastatic melanoma
with a durable response profile,7 is being investigated in several
clinical trials. In a setting of a phase III clinical trial of 951
resected stage III patients, ipilimumab is being compared to
placebo in a 1:1 fashion. After a median follow-up of 2.7 years,
3-year progression-free survival rates were significantly higher
Surgical Implications of Systemic Therapy for Skin Cancer
162

in ipilimumab group (46.5 vs. 34.8%, p =0.0013).51 The higher
dose of ipilimumab (10 mg/kg) used in this trial has resulted in
a considerable grade 3/4 adverse event rate, particularly for
endocrinopathies (8.5 vs. 0%). Of the patients started on ipili-
mumab, 52% discontinued treatment because of adverse events,
most within 12 weeks of therapy initiation. Other phase II and
phase III clinical trials investigating adjuvant ipilimumab are
currently accruing patients.52,53
8.4 Systemic Therapy of
Nonmelanoma Skin Cancer
8.4.1 Cetuximab
The vast majority of patients diagnosed with cutaneous squa-
mous cell carcinoma have excellent prognosis, and surgical
resection is usually su cient therapy. However, in approxi-
mately 5% of the 700,000 annual cases, there are high-risk fea-
tures that can result in regional and/or distant metastases.
These high-risk features include size ≥2 cm, thickness ≥4 mm,
head and neck location, poor di erentiation, perineural inva-
sion, tumor recurrence, and host immunosuppression.4,54,55
Patients w ith these advanced squamous cell carcinom as have
5-year survival rates of 65 to 75% in the presence of regional
m etastases.56,57
Adjuvant therapies have been studied in attempts to improve
upon the relatively poor survival outcomes with surgery alone
for squamous cell carcinoma with regional metastatic disease.
Cetuximab has been explored with some success for such a
purpose. In a setting of a phase II clinical trial of 36 chemother-
apy (naive unresected patients), cetuximab demonstrated an
objective response rate of 28%, with a disease control rate of
69% and a progression-free survival of 4.1 months.58 The most
common side e ect was a rash, with no patient presenting with
grade 3/4 toxicity. Other uncontrolled studies have shown a
reduction in morbidity via tumor regression following cetuxi-
mab therapy, and associated improved clinical outcomes.59,60
The limited data indicate potential for reducing morbidity of
resection and improving survival, but larger well-designed con-
trolled trials are needed to further confirm these outcomes.
8.4.2 Hedgehog Inhibitors
Basal cell cancer is the most common cutaneous malignancy.1
These tumors rarely develop metastases but may grow locally,
causing significant morbidity and disfigurement if not treated
properly. Given these circumstances, an e ective treatment had
not been available until 2012, when vismodegib, a hedgehog
inhibitor, was approved by the FDA. Most basal cell carcinomas
have abnormalities in the hedgehog signaling pathway, and vis-
modegib inhibits signaling by blocking the activity of smooth-
ened homologue. In a phase II clinical trial of 96 patients,
vismodegib was shown to be e ective for metastatic basal car-
cinoma (objective response rate of 30%, p =0.001) and advanced
basal carcinoma (objective response rate of 43%, p <0.001).61
The median progression-free survival was 9.5 months in both
cohorts. The toxicity profile was significant, with serious
adverse events occurring in 25% of patients. There were also
seven deaths, although no definite pattern was identified, with
the authors stating that the relationship between the study
drug and the deaths was undetermined. This agent has also
shown e cacy in preventing the development of new cancers
in patients with basal cell nevus syndrome, although the
adverse events were significant enough to warrant therapy dis-
continuation in approximately half of the patients.62
8.5 Implications of Systemic
Therapy for the Surgeon
The surgeon may be called upon to help manage patients with
metastatic melanoma with the goal of curative resection, pallia-
tive intervention, or management of complications from sys-
temic therapy. Melanoma patients should be carefully
evaluated for the ability to completely resect all tumor, the
underlying metabolic and nutritional status of the patient,
medical comorbidities, and the potential for durable responses
with previous and subsequent systemic therapy. In general,
patients should first be evaluated for curative operation, and if
this is deem ed not possible, then the goal may be palliative or
designed to improve the patient’s quality of life.
8.5.1 Surgery for Metastatic Disease
Over the past two decades, the role of surgery in the treatment
of metastatic melanoma has continued to expand. Palliative
resection of impending small bowel metastases and painful
cutaneous lesions has become an accepted practice, with con-
siderable retrospective reports suggesting clinical benefit and
improvement in quality of life. Melanoma is the most common
malignancy to metastasize to the small intestine, and reports of
solitary and oligometastatic gastrointestinal metastasectomy
have been associated with improved survival when compared to
incomplete resection or observation.63,64,65,66 Similarly, retro-
spective reports of curative resections for cutaneous, nodal, and
pulmonary metastases have shown improved outcomes with
surgery. The patients who benefitted most from an operative
approach were those with a limited number of metastases that
could be excised completely. These patients were associated with
a long progression-free interval from the time of diagnosis.67,68
The role of metastasectomy was explored in a large cohort of
patients who were enrolled in the Multicenter Selective Lym-
phadenectomy Trial-1 (MSLT-1). In this study, 291 patients
developed metastatic disease. Metastasectomy was performed
in 161 of these patients, and the 4-year survival rate was supe-
rior in this group than in a comparable nonoperated group
(20.8 vs. 7%, p <0.0001).69 Operations were most beneficial in
patients with stage M1a disease (cutaneous, subcutaneous, and
nodal metastases). Curative resections have also been shown to
be e ective in improving survival of carefully selected patients
with visceral oligometastatic disease, including brain, liver, and
adrenal gland metastases.70,71,72 A cohort of patients who
underwent resection of brain metastases had a median survival
of 8.5 months, which is an improvement over the expected 3-
to 6-month survival in patients treated nonoperatively.70
More recently, the concept of considering metastasectomy in
patients with an incomplete response to systemic therapy has
been established. This has gained support due to the larger
number of e ective systemic agents and the durability
Surgical Implications of Systemic Therapy for Skin Cancer
163

associated with newer treatment regimens, most notable
immunotherapy approaches. Data supporting the benefit of this
strategy have been demonstrated in several small-cohort
reports. Eleven patients with metastatic renal cell carcinoma
treated with high-dose IL-2 had a partial response. These
patients subsequently underwent an excision of residual dis-
ease in order to be rendered surgically no evidence of disease
(SNED). Progression-free survival of these patients was compa-
rable to complete responders and was found to be superior to
partial responders who did not undergo operative intervention
(100 vs. 76 vs. 35%).73 Similar results were demonstrated for
progression-free survival in 60 patients who were partial re-
sponders to IL-2 with metastatic melanoma and renal cell carci-
noma.74
With the recent introduction of more potent
immunotherapy agents, such as ipilimumab and PD-1 and PD-
L1 inhibitors, the approach of resecting residual disease with
the intention of SNED in partial responders is likely to improve
outcomes in a greater number of patients.
While metastasectomy for melanoma has been evaluated in
retrospective series, there are even fewer reports on the role of
metastasectomy for squamous cell carcinoma or other types of
skin cancer. The use of cetuximab can result in objective, yet
incomplete, clinical responses, and it is appropriate to consider
resection of residual disease in those patients who exhibit a
profound initial response to such therapy. Until further studies
can be done, it is appropriate that patients with metastatic skin
cancer who have incomplete responses to current systemic
treatments be considered for resection of residual disease,
especially if complete extirpation of all disease is possible.
8.5.2 Surgical Management of Toxicities
of Systemic Therapies
The number of systemic agents available for the treatment of
metastatic melanoma has increased with seven new agents
approved by the U.S. FDA between 2011 and 2015. These drugs
include molecularly targeted agents and immunotherapy drugs,
which are both associated with unique side e ects as discussed
earlier. The surgeon may be placed in a position to manage vari-
ous toxicities, although algorithms for standard management
are not established. The most common surgical issues associ-
ated with systemic melanoma therapy are autoimmune gastro-
intestinal toxicities seen with immunotherapy and the
management of squamous cell carcinomas in patients treated
with BRAF inhibitors.
Ipilimumab has been associated with autoimmune enteroco-
litis, and occurs in about 21% of patients when the drug is used
at the 3 mg/kg dose.75 A higher rate of colitis has been reported
with higher doses of ipilimumab, and lower rates of colitis have
been seen with inhibitors of the PD-1/PD-L1 pathway. In gen-
eral, colitis can be managed medically with antidiarrheals for
limited symptoms. More serious or resistant cases can require
high-dose corticosteroids and rarely infliximab. In all cases of
significant diarrhea, management should include excluding
other causes of colitis, such as Clostridium di cile–associated
colitis, and e orts to rule out perforation should be done prior
to initiating high-dose immunosuppressive medication.
Although medical management is usually e ective for auto-
immune colitis, about 2% of patients with ipilimumab-related
colitis will develop bowel perforation. The surgeon should be
aware of this di cult complication given its diagnostic chal-
lenges because many of the patients will already be on high
doses of corticosteroids, potentially masking overt symptoms of
an acute abdomen. Diarrhea and hematochezia are common,
but not uniformly associated with autoimmune colitis related
to tumor immunotherapy. Some patients can present with
crampy abdominal pain without diarrhea. If there is doubt
about the status of such patients, admission with serial abdomi-
nal examinations, fluid/electrolyte monitoring, repeat white
blood cell counts, and consideration of intra-abdominal imag-
ing should be performed. Patients may also require gentle
endoscopy and a low threshold for surgical intervention.
The surgical approach to ipilimumab-related bowel perfora-
tion has not been uniformly established. A thorough explora-
tory laparotomy should be completed to ensure that there are
no other causes for the colitis, and laparoscopy may be helpful
as an initial approach. If the site of perforation can be identified
either preoperatively or intraoperatively, primary repair may
be possible if there is minimal contamination of the peritoneal
cavity. Intraoperative endoscopy can also be a useful aid when
the site of perforation is not known. In the event that the site
cannot be found, a total colectomy may be necessary. Diversion
may also be required depending on the degree of intraperito-
neal contamination, status of the bowel, and security of the
repair. Copious intraperitoneal irrigation should also be per-
formed prior to closure. Patients may require stress doses of
steroids if they have been on immunosuppressive agents for a
prolonged time prior to operation. While the role of antibiotics
has not been firmly established, early and perioperative antibi-
otics should also be considered in the management of severe
autoimmune colitis once C. di cile colitis has been excluded.
Colonic perforation has also been reported with other forms
of immunotherapy, although the incidence is much lower with
PD-1 inhibitors and has been reported to occur in less than
0.45% of patients treated with high-dose IL-2 therapy.76 Ipilimu-
mab followed by high-dose IL-2 has even led to a bowel perfora-
tion rate of 13.6%.77 Some clinicians recommend a colonoscopy
after therapy with ipilimumab, but prior to the initiation of a
second agent, such as IL-2, to rule out active colitis if patients
have symptoms.37 As di erent combination regimens continue
to be evaluated, it is important for both the medical oncologist
and the surgeon to remain vigilant and knowledgeable about
possible complications of such therapy.
A unique side e ect of BRAF inhibitor therapy is development
of cutaneous acanthomas and, rarely, invasive squamous cell
carcinoma. This has been observed with both vemurafenib and
dabrafenib treatment.78 While most of the cutaneous lesions
that develop secondary to treatment with these agents are
benign acanthomas, the potential for invasive squamous cell
carcinoma mandates that all patients on BRAF inhibitor therapy
have regular skin screening by a qualified dermatologist, who is
comfortable di erentiating between these two entities. Typi-
cally, the cutaneous lesions arise after 3 months of treatment,
but can occur as early as 1 week into therapy. The incidence of
squamous cell carcinoma has been reported to be as high as
Surgical Implications of Systemic Therapy for Skin Cancer
164

26% in some series.79 Large or painful benign acanthomas or
documented invasive carcinomas should be treated by complete
surgical excision. While metastases have not been reported,
treatment should generally be discontinued or reduced and
patients monitored more closely once a serious cutaneous
manifestation has occurred. Interestingly, combination therapy
with a BRAF and MEK inhibitor lowers the incidence of
both benign and malignant cutaneous lesions, and the e ect is
dose-dependent.9,25
8.6 Conclusion
The impact of skin cancer continues to grow. Melanom a is
now the fifth-m ost com m on malignancy in the United
States, w hile the incidence of nonmelanom a skin cancers is
higher than all the other cancers com bined. The grim out-
look for patients with advanced nonmelanom a skin cancer
and metastatic m elanoma is quickly changing because of the
rapidly expanding arm amentarium of agents available for
systemic treatm ent. In addition to cytotoxic chem otherapy,
there are an increasing num ber of new m olecularly targeted
therapy and im m unotherapy agents available. The targeted
therapy drugs have rapid onset and high response rates,
although resistance is nearly universal. In contrast, tum or
im munotherapy agents m ay take a longer time for a res-
ponse to develop, but can induce very durable responses.
The implications for the surgeon are two-fold. As the e ec-
tiveness of system ic therapy has improved the outcom es for
patients with advanced and m etastatic skin cancer, metasta-
sectomy of all residual disease in patients with incomplete
responses to systemic therapy m ay be advisable. Addition-
ally, surgical complications of targeted therapy include
benign and m alignant skin neoplasms requiring surgical
excision and careful skin surveillance. Im munotherapy, m ost
notably with ipilimum ab and combination approaches, has
resulted in autoimm une colitis that may require careful clin-
ical m anagem ent and rarely surgical exploration and colec-
tomy for bowel perforation. The surgeon will continue to be
an important part of the team involved in caring for patients
w ith m etastatic m elanoma and nonm elanoma skin cancer
while on system ic therapy.
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96(3):552–558
[71] Mittendorf EA, Lim SJ, Schacherer CW, et al. Melanoma adrenal metastasis:
natural history and surgical management. Am J Surg. 2008; 195(3):363–368,
discussion 368–369
[72] Ryu SW, Saw R, Scolyer RA, Crawford M, Thompson JF, Sandroussi C. Liver
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9 Common Reconstructive Techniques after Facial Skin
Cancer Excision
Neilendu Kundu and Brian R. Gastman
9.1 Introduction
Skin cancer represents a diverse collection of pathology. Skin
cancer is the most common cancer in the United States, and it is
estimated that 20% of Americans will develop at least one skin
cancer in their lifetime.1,2 According to published figures, the
average annual treatment cost for skin cancer in the United
States was approximately $8.1 billion from 2007 to 2011.2 This
figure continues to rise annually.
A large subsection of skin cancer a ects the face, given it is
one of the areas that is most exposed to the elements. Cutane-
ous defects of the face are unique for a variety of reasons. From a
medical science standpoint, wounds tend to heal very well with
a low rate of infection and often require minimal debridement
compared to other areas of the body due to the exceptional vas-
cularity of the face. As will be discussed later, cosmetically
acceptable results can be achieved even with secondary inten-
tion. From a social science standpoint, the face is critical for com-
munication, as well as negotiating complex social interactions
that are part of daily activity. Thus, reconstruction of lesions of
the face is crucial for patients to maintain normalcy. Tagliacozzi
—one of the fathers of plastic surgery—described it best, “restore,
repair, and make whole those parts which nature has given, but
fortunate has taken away, not so much that it please the eye of
the beholder, but that it buoys the spirit of the a icted.”3
Facial reconstruction allows for contributions from a range of
specialties, including general and plastic surgery, dermatology,
ophthalmology, and otolaryngology. In order to appropriately
manage these defects, a multitude of options are necessary in
the surgeon’s armamentarium. This requires exposure to exten-
sive modalities from primary closure to skin grafting to locore-
gional flaps and even free tissue transfer. While some
reconstructive options extend beyond the scope of this chapter,
common techniques are described, including pitfalls to avoid.
The face is one of the most anatomically complex aspects of
the body. To aid surgeons in better elucidating areas of recon-
struction, it has been divided into facial aesthetic regions based
on landmarks and shadowing. The main aesthetic subunits of
the face include the forehead, eyelids, cheeks, nose, lips, chin,
and ears.4 These subunits are then subsequently further subdi-
vided. For example, the nose itself has nine subunits: the dor-
sum, paired lateral side walls, tip, paired soft tissue triangles,
paired lobules, and the columella.5 The ideal reconstruction for
cutaneous defects provides coverage with like tissue, ideally
from within the aesthetic unit itself. By manipulating the subu-
nit principle, scars can be “hidden” within natural shadows to
provide aesthetically pleasing outcomes for patients who
present with initially intimidating facial defects.
9.2 Forehead
Experience in forehead reconstruction has revealed that large
defects can be primarily closed with excellent results.
Additionally, due to the rich vascularity, defects can also heal
with secondary intention yielding cosmetically satisfying
results ( Fig. 9.1). The forehead has been subdivided into para-
median, lateral, and lateral temporal subunits, with the eye-
brows providing a mobile subunit of their own.6
Arterial and venous flow is provided by paired vessels. From
the arterial standpoint, flow is distributed from both the exter-
nal and internal carotid arteries by the paired frontal branches
of the superficial temporal artery (external carotid artery sys-
tem) and supratrochlear and supraorbital arteries (internal car-
otid artery system). Each supply is robust enough to allow for
elevation of a flap utilizing this as the axial system. This allows
for a variety of rotation and advancement flaps.
The forehead is innervated by the supraorbital nerve as well
as by the frontal branch of the facial nerve. The supraorbital
nerve provides sensory innervation to the forehead and has
two divisions. There is a deep division that runs from the orbital
rim (lateral) toward the superior temporal line of the skull,
which then moves cranial (parallel) to the temporal line before
taking a medial course to enter the scalp. The superficial divi-
sion also courses over the orbital rim, but traverses anterior to
the frontalis muscle to provide sensation to the scalp. Injury to
these nerves can lead to paresthesias as well as itching. The
frontal branch of the facial nerve is deep to the frontalis—which
it innervates. It provides motor function and can be identified
along a line—referred to as Pitanguy’s line—that runs 0.5 cm
below the tragus to a point 1.5 cm superior to the lateral posi-
tion of the eyebrow.7
Small defects of the forehead—up to 1 to 2 cm—can be closed
primarily or heal with secondary intention with satisfactory
cosmetic results. This concept has been utilized in nasal recon-
struction, where forehead flaps have been utilized for large
nasal defects. The superior aspect of the forehead flap—which is
based on an axial blood supply from the supratrochlear system
—is left open to allow for granulation and healing. With stand-
ard wound care to ensure maintenance of a clean, moist envi-
ronment, the forehead scarring is acceptable. The downside to
leaving the wound open is that it may take up to 6 weeks to
achieve complete healing.
Medium-sized defects of the forehead—up to 3 to 4 cm—can
be approximated with primary closure. Primary closure of
larger wounds is possible in this region due to the excellent vas-
cularity. Wounds that may otherwise develop wound necrosis
elsewhere on the body due to tension on the incision often heal
without complication.
For relatively large defects of the forehead—up to 6 cm —
advancem ent flaps provide excellent outcomes as they
m obilize skin from relaxed skin tension lines (RSTL) of the
forehead. While full-thickness, sheet skin grafts are also
excellent options, “H-flaps” allow for reconstruction w ithin
the aesthetic principle without utilization of a separate
donor site. H-flap also utilizes the benefit of increased laxity
found w ithin the lateral forehead skin, w hich helps to facili-
tate m obilization. In prospective case series studies, H-flap
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was found to have excellent cosm etic outcomes based on
answers to a validated patient satisfaction questionnaire.8
The flap is created by m aking incisions parallel to the RSTL
and removing burrow triangles from each side. After
rem oval of the triangles and underm ining superficial to the
temporal m uscle to decrease the likelihood of injury to the
supraorbital nerves, the wounds can be closed w ithout
undue tension, also allowing for aesthetic scars ( Fig. 9.2).
The cosm esis can be improved further by designing the flap
in such a way that the horizontal components are able to fit
w ithin the main transverse rhytids of the forehead that are
created due to the natural movem ent of the frontalis
m uscle.
Temporal wounds of the forehead can also be reconstructed
using local advancement flaps, as described earlier. A key aspect
in this region is to maintain the position of the eyebrow as well
as the temporal hairline. Regional flaps—including the cervico-
facial flap, which will be discussed in detail later in this chapter
—can provide one with the ability to solve both of these poten-
tial situations before they become an issue.
9.3 Cheeks
The cheek possesses the largest facial aesthetic region and is
intimately related to social interaction as it allows for the ability
to capture emotion on a large scale, in conjunction with the
other aspects of the face. It marries the superior and inferior
face to act as one unit.
Contour of the cheek is created by a synergy of fat distribu-
tion, underlying bony architecture, and the retaining ligaments
of the face. Retaining ligaments of the cheek are critical for
these subunits as they provide the structural framework that
allows for youthful appearance. Thus, as one ages, these
ligaments become increasingly lax, which can cause fat redis-
tribution, leading to an older appearance. Several of these
retaining ligaments have been described which has allowed for
classification of the aforementioned creases. For example, the
retaining ligaments of the zygoma have been referred to as
McGregor’s patch. These are osteocutaneous ligaments that
provide support for the skin overlying the zygoma. Other exam-
ples include ligaments at the junction of the cheek and upper
Fig. 9.1 (a,b) Secondary healing of a forehead after a paramedian forehead flap utilized for nasal reconstruction is common practice. Often,
acceptable cosmetic results can be obtained using this method for the forehead. (c) The superior aspect was left to heal with secondary intention
leaving a cosmetically acceptable result.
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169

lip creating the melolabial (nasolabial) crease.9 The anatomy of
the cheek requires knowledge of the facial nerve as well
because injury can be severely disfiguring for patients. As long
as dissection proceeds anterior to the superficial musculo-
aponeurotic system (SMAS), a safe plane—with respect to the
nerves—is maintained.
The cheek receives its vascular supply from the external caro-
tid system. Namely, it obtains the majority of its blood flow
from branches of the facial artery. A minor supply is provided
by the transverse facial artery, which is a branch of the super-
ficial temporal artery. The venous drainage follows the arterial
system, as it does in the forehead.
Innervation to the cheek is dependent on location. The
medial aspect of the cheek from just lateral of the lateral limbus
to the upper second premolar tooth is supplied by the infraorbi-
tal nerve (from the second division of the trigeminal cranial
nerve). The nerve also provides sensation to the lower eyelid,
upper lip, and nasal vestibule. The anterior branch of the great
auricular nerve provides sensation for the lateral skin from the
tragus to the lateral limbus.
Several classification systems of the cheek have been devel-
oped that divide the cheek into separate aesthetic subunits.
One utilizes eight separate aesthetic subunits. They are the
inferior bony orbital rim, nasofacial sulcus, melolabial crease,
labiomandibular crease, inferior border of the mandible, pre-
auricular crease, and a line extending from the lateral canthus
to the root of the helix.9 Roth et al divided the cheek into three
overlapping aesthetic zones: zone 1 (suborbital), zone 2 (pre-
auricular), and zone 3 (buccomandibular).10 Based on these
zones, reconstructive algorithms for the cheek have been
described. Fig. 9.3 reveals an algorithm that is easy to follow
in this author’s opinion.11 Many defects of the cheek—including
a high percentage of Mohs defects—can be reconstructed using
primary closure. An elliptical excision or simply creating
Fig. 9.2 A 2-cm squamous cell carcinoma excised leaving a 6-cm defect approximated with an H-flap under local anesthesia.
ent
Fig. 9.3 An easy-to-follow cheek reconstruction algorithm. (Reproduced with permission from Rapstine et al.11)
Common Reconstructive Techniques after Facial Skin Cancer Excision
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Burow’s triangles at both ends of a Mohs defect, in the plane
that is best fitting with the RSTL, allows for tension-free, pri-
mary closure with optimal cosmetic results. This is especially
the situation in older patients because there is an increase in
the amount of skin laxity, thus allowing for repair without con-
cern for issues including ectropion or elevation of the modiolus.
Small defects that abut the nose/lip or chin can be closed
using crescentic advancement, bilobed/VY advancement, or
nasolabial fold flaps.
For patients who have large defects of the cheek—more than
3 to 4 cm—several options for reconstruction are feasible. While
tissue expansion is an appropriate option and can lead to excel-
lent results, it requires several weeks to months of painful
expansion as well as substantial disfigurement in the time
frame until the expansion process has reached its completion.
Additionally, custom-made expanders are often required for
the cheek, which can cause an increase in cost. Full-thickness
skin grafting, harvested from the pre/postauricular or
supraclavicular sites, provides a reasonable reconstructive op-
tion for older patients who possess multiple comorbidities. Skin
grafting is not the preferred option given that it can be di cult
to obtain a good color match with the native face. Furthermore,
contracture of the skin graft can also lead to suboptimal results.
Originally described by Mustarde for lower lid reconstruction,
cervicofacial advancement flaps provide the ability to cover a
large surface defect of the skin with tissue that possesses an
ideal color, texture, and contour match.12 Austen et al described
32 consecutive cervicofacial flaps that were performed without
major complications and with satisfactory cosmetic results.13
Additionally, dissection can be carried inferiorly beneath the
neck to the level of the deltopectoral groove to assist in the
recruitment of additional tissue for tension-free repair. This is
of importance for wounds that are large and also are near the
medial canthus, where excess tension of the wound can lead to
ectropion (Fig. 9.4). A significant aspect in the reconstructive
decision tree is choosing between a cervicofacial and reverse
Fig. 9.4 An 8 × 8 cm cheek defect that was reconstructed using a cervicofacial flap.
Common Reconstructive Techniques after Facial Skin Cancer Excision
171

cervicofacial advancement flap.14 The di erence between the
two types of flap stems from the directionality of the rotation.
A cervicofacial flap rotates the lateral cheek and neck skin
toward the nose. The reverse cervicofacial flap rotates the skin
of the lower face in a cranial direction. The reverse flap is used
in situations where the defect is medial to the midpupillary line
(Fig. 9.5).
Marking the cervicofacial flap requires a preauricular facelift
incision that can be extended behind the ear and inferiorly
toward the deltopectoral groove. The superior aspect of the
marking should be above the level of the lateral canthus, as this
is the point of maximal tension and can produce an ectropion if
marked beneath the canthus. The incision can then be extended
medially toward the defect. Elevation the flap is above the
SMAS and can transition to a subplatysmal dissection in the
neck for recruitment. A large standing cone (“dog ear”) can then
be excised in the medial aspect, which allows for appropriate
insetting of the flap. However, one needs to be certain not to
encroach into the base of the flap while excising the dog ear. If
there is concern, then keep the standing cone and return in sev-
eral weeks as division. As the flap can be large, a drain is usually
placed and left until the output is less than 30 mL over a 24-
hour period.
9.4 Eyelids
Eyelids are arguably the most complex facial subunits with
respect to reconstruction due to the intricate interplay of muscu-
lature and thin skin. Besides being the thinnest skin in the body,
the lids service as vital barriers that protect, lubricate, and clean
the eyes.15,16 The basic principles of reconstruction include
maintenance of the aforementioned key functions for eye pro-
tection, as well as maintenance of eye mobility, using like tissue
for replacement of deficiencies in soft tissue, all the while main-
taining aesthetics. Local flaps and grafts serve as the workhorses
Fig. 9.4 (continued)
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172

for the reconstructive surgeon (Fig. 9.6). However, due to the
complexity that is beyond the scope of this chapter, we will
forego additional discussion regarding specific eyelid techniques.
9.5 Lips
The lips play a major functional role in sensation, facial
expression, oral continence (including muscular integrity),
and phonation, while serving as the focal point of the lower
face. The lips interplay several aesthetic units, which are com-
posed of skin, muscle, and mucosa. This can be particularly
challenging from a reconstructive standpoint as it is di cult
to produce tissue of the same quality, color, texture, etc.,
utilizing distant flaps.17 Lip alignment needs to be precise
as minute distortion of the vermilion—even at the level of
1 mm—can lead to obvious scarring that can be seen at con-
versation distance.18
The lip is divided into two aesthetic units: upper and lower
lip. The upper lip has two units—the lateral and medial/philtral.
The lower lip is one entire aesthetic unit itself. The external
landmarks are the commissure, cupid’s bow, philtral columns,
tubercle, white roll, and red roll. Additionally, there are four key
components. They are the skin and subcutaneous tissue, muscle
(orbicularis oris), mucosa, and the vermilion border. From a
cross-sectional standpoint, innervation—which consists of the
mental and infraorbital nerves for sensation, as well as the infe-
rior orbital nerve (upper) and the mental nerve (lower) for
motor innervation—and vascular supply (labial artery branches
of the facial artery) lie between the muscle and mucosa. The
vermilion is the visible portion of the lip within the outer white
roll and has a unique light reflection.19 One of the key hallmarks
to reconstruction of the lip is maintenance of this vermilion
border.
Full-thickness lip reconstruction is carried out using the rule
of thirds.20 For the sake of this chapter, full-thickness complete
Fig. 9.5 A reverse cervicofacial flap can be used in situations where there exists large defects medial to the midpupillary line.
Common Reconstructive Techniques after Facial Skin Cancer Excision
173

Fig. 9.6 A Cutler-Beard flap for upper eyelid reconstruction. (Subparts i and j reprinted with permission from CCF.)
Common Reconstructive Techniques after Facial Skin Cancer Excision
174

defects of the lips will be omitted. Free flap reconstruction with
innervated, free radial forearm and palmaris longus has been
the standard reconstruction modality for many years.21,22 If the
defect totals less than one-third of the lip, then primary closure
can be performed with wedge excision. To obtain ideal results,
one needs to ensure precise approximation of the tissues—
including the vermilion border (Fig. 9.7).
For defects that encompass between one-third and half of
one lip with commissure preservation, one can utilize a staged,
Abbe lip switch flap23 (Fig. 9.8). Prior to performing an Abbe
flap, the patient needs to be alerted to the lack of postoperative
sensation. When designing the flap, marking should be half the
width of the defect to ensure the ability to close the donor site
primarily. The flap is performed in a full-thickness manner
through the mucosa and pivoted nearly 180 degrees on its
pedicle. The patient is able to have parenteral nutrition limited
to liquids until flap sectioning, which occurs usually in 3 weeks.
Flap viability is evaluated prior to sectioning by compressing
the flap to eliminate flow and evaluating the viability of the tis-
sue that has been transplanted.
Fig. 9.6 (continued)
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175

When defects involve the com missure and are less than
half of the total width of either the upper or lower lip, then
an Estlander flap can be perform ed.24 While the flap is
insensate—like the Abbe—it also su ers from distortion w ith
oral anim ation as the m odiolus is altered ( Fig. 9.9). This
can often require secondary comm issuroplasty. Sim ilar to
the Abbe, the donor site needs to be designed in a full-
thickness manner and should be one-third to one-half the
size of the defect.
Fig. 9.7 Lip advancement flaps can be utilized to obtain excellent aesthetic results. Precise vermillion border approximation is the most critical aspect.
Common Reconstructive Techniques after Facial Skin Cancer Excision
176

Fig. 9.8 An Abbe lip switch staged flap can be used for defects that encompass one-third to one-half of one lip.
Common Reconstructive Techniques after Facial Skin Cancer Excision
177

Fig. 9.9 When defects involve the commissure, an Estlander flap reconstruction can often be utilized to provide excellent reconstructive outcomes.
These flaps can be used for defects that encompass half the total width of either one of the lips while simultaneously involving the commissure.
Common Reconstructive Techniques after Facial Skin Cancer Excision
178

Central defects involving one-third to two-thirds of the lip
can be reconstructed using a Karapandzic flap25 ( Fig. 9.10).
While larger defects that utilize a Karapandzic flap can lead to
microstomia, the flap is ideal in that it is performed in a single
stage that maintains competence of the oral sphincter as well as
the modiolus and philtrum. Additionally, the flap is able to
maintain sensation unlike the Estlander and Abbe flaps. Mark-
ing of this flap requires the width of the curvilinear incision to
maintain—at a minimum—the height of the vertical component
of the defect. This allows for appropriate rotation of the cir-
cumoral flaps to approximate the defect without substantial
tension, all the while allowing for closure of the curvilinear
incisions.
9.6 Nose
The nose occupies the most crucial place of the face as it occu-
pies the (0,0) space from a Cartesian coordinate system stand-
point. Alterations and changes to the nose can lead to poor
cosmetic outcomes and, worse, compromised breathing if the
deeper structures are involved. As discussed earlier in the
chapter, the nose is subdivided into nine aesthetic subunits: the
dorsum, the paired lateral side walls, tip, paired soft tissue tri-
angles, paired lobules, and the columella.5 One of the key con-
cepts regarding nasal subunits for reconstruction is the
emphasis on replacement of an entire subunit if the majority of
one is missing. While it may seem counterintuitive, this may
lead to making the wound larger. This concept has been
stressed by Menick and relies on the principle of hiding inci-
sions within the shadows created by the natural contours of the
nose, thus increasing the camouflage to distract the eye.26
The nasal skin thickness and character vary in a cranial to
caudal dimension with the skin becoming thicker with more
sebaceous glands and less pliable when moving further caudally
toward the tip. Additional di erences are noted between the
skin of men and women—with men having more glabrous and
thicker skin. All of these factors dramatically a ect the recon-
structive options. Depth of defects a ects the reconstructive
modalities that would pertain to the best outcomes. For the
majority of cutaneous malignancies, defects will be limited to
the full thickness of the skin and subcutaneous tissues. Yet,
there are situations in which deeper structures, such as
Fig. 9.9 (continued)
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179

Fig. 9.10 Large central lip defects are reconstructed using Karapandzic flaps. However, care needs to be exercised as patients can develop
microstomia.
Common Reconstructive Techniques after Facial Skin Cancer Excision
180

cartilage, are required to be removed during the extirpation.
These defects are often not the situation when discussing nasal
cutaneous malignancies. As such, we will not discuss, in-depth,
wounds that involve cartilaginous and mucosa reconstruction
because they are beyond the scope of this chapter.
While the workhorse of cutaneous nasal reconstruction
stems from local flaps, full-thickness skin grafts (FTSGs) are of
instrumental assistance to provide a reconstructive modality
that is time e cient, which is a substantial benefit in patients
who have a multitude of comorbidities. One of the key benefits
of FTSGs is the ability to reconstruct nasal defect of almost any
size. The most common locations for donor sites for color match
include the pre- and postauricular skin as well as the supracla-
vicular skin. Additional sites, including the medial arm and
groins, can also be used if there is substantial actinic damage or
prior scarring to the aforementioned locations. Ideally, the
nasal defect would be superficial as well as smaller than an aes-
thetic unit. Superficial wounds have improved vascularity,
which increases the likelihood of graft take. Furthermore, the
lateral aspects of the nose, which are thin by nature, tend to fill
in well. This is an important characteristic given there is a wide
variation in the nasal skin thickness among individuals. As a
broad rule of thumb, skin grafting can be utilized to reconstruct
the cranial nose. Typically, because the tip skin is thicker, graft-
ing may not provide as ideal an outcome as a local flap. FTSGs
are utilized instead of split-thickness skin grafts (STSGs) due to
the improved color and texture match with nasal skin. The
main drawbacks are the requirement of a donor-site repair and
decreased graft take compared to STSGs. Furthermore, skin
grafting on areas near the nostrils can lead to upturning due to
contracture of the nostril; thus, flap reconstruction near this
area is more often considered the norm.
While small defects of around 1.0 cm in size can be closed
primarily—either in the transverse or vertical dimension—
wounds of up to 1.5 cm often benefit from closure using a
bilobed flap.27 The bilobed flap is a random-pattern, single-
stage flap that rotates two adjacent lobes about a pivot point.28
The first lobe of the flap is rotated into the defect and the sec-
ond lobe is rotated into the wound created by the movement of
the first lobe. The defect left by the second lobe is closed pri-
marily ( Fig. 9.11). The key concept is in the planning and
design. The markings begin by drawing a perpendicular to the
wound along the axis that is planned—typically in the vertical
dimension. The first lobe is drawn adjacent to the wound and
Fig. 9.10 (continued)
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181

Fig. 9.11 A bilobed flap can be used for
nasal reconstruction in wounds up to 1.5 cm.
Common Reconstructive Techniques after Facial Skin Cancer Excision
182

designed to be slightly smaller than the defect. The second lobe
is drawn approximately 45 degrees from the first lobe with the
primary lobe axis positioned 45 degrees from the axis of the
defect, ideally within the sidewall or upper dorsum. Zitelli
stated that no more than 50 degrees of rotation should be
designed for each lobe. Additionally, the burrow triangle
between the defect and the pivot point should be excised prior
to rotation.27 The elevation of the flap is supraperichondrial
plane. One needs to ensure that there is appropriate dissection
—oftentimes more than one would think—to ensure adequate
rotation of the flap without tension. The first lobe is rotated in
place to close the defect followed by the second lobe rotation.
The wound is closed in an interrupted manner using 6–0 mono-
filament sutures.
For defects that are between 1.5 and 2.5 cm in size, dorsal
nasal flaps provide the ability to recruit the redundant skin of
the glabella and can be used for defects of the tip, dorsum, and
sidewall ( Fig. 9.12). It is based laterally and elevated on the
angular arteries. This flap is ideal in older patients given it max-
imizes the laxity of their skin.29 Like the bilobed flap, the plane
of dissection is above the perichondrium. The superior triangle
is removed, and after the flap is elevated, it is rotated in place
with a broad base. The common disadvantages of this flap are
tip elevation/rotation and elevation of the ala in lateral nasal
defects.
The nasal ala is a critical structure in nasal reconstruction
because notching can be seen readily. This can be avoided with
the use of a nasolabial advancement flap. Additionally, the cau-
dal one-third of the nose—which is the area of the highest con-
centration of cutaneous malignancies—can be reconstructed
almost entirely by this flap, though additional cartilage grafting
may be required for alar support.30 The nasolabial flap is versa-
tile in that it can be designed either superiorly or inferiorly
based on the branches of the facial artery. When placed within
the nasolabial fold, the donor site is provided excellent camou-
flage for an ideal cosmetic result (Fig. 9.13 and Fig. 9.14).
Fig. 9.12 A dorsal nasal flap can achieve excellent aesthetic results for appropriate defects. Here are multiple views of an early follow-up patient.
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183

Fig. 9.13 Nasolabial fold flaps allow for excellent camouflage for nasal reconstruction.
Common Reconstructive Techniques after Facial Skin Cancer Excision
184

Fig. 9.13 (continued)
Common Reconstructive Techniques after Facial Skin Cancer Excision
185

Fig. 9.14 Another patient with a nasolabial fold flap, which provides versatile soft tissue coverage for alar rim reconstruction.
Common Reconstructive Techniques after Facial Skin Cancer Excision
186