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Australasian Journal of Dermatology (2014) ,

doi: 10.1111/ajd.12263

ORIGINAL RESEARCH

Radiotherapy alone in patients with Merkel cell

carcinoma: The Westmead Hospital experience of
41 patients
Michael Veness1 and Julie Howle2
Departments of 1Radiation Oncology and 2Surgical Oncology, Westmead Cancer Care Centre, Westmead
Hospital, University of Sydney, Sydney, New South Wales, Australia

INTRODUCTION
ABSTRACT
Objectives: To review the role of radiotherapy as
treatment (RTx) alone in patients with Merkel cell
carcinoma (MCC).
Methods: Data on 41 patients with MCC treated
with RTx alone between 1993 and 2013 at Westmead
Hospital, Sydney, were reviewed and analysed.
Results: The patients median age was 80 (range
4596 years) among 18 (44%) women and 23 (56%)
men. All but one patient were white and six (15%)
were immunosuppressed. Most (59%) were irradiated at initial diagnosis with the remainder treated in
the relapse setting. The median duration of follow up
was 39 months. Head and neck was the most frequently treated site (63%). The median lesion size
was 30 mm (range 5130 mm). The in-field control
rate was 85%. Most out-of-field relapses were to visceral organs. Overall survival at 5 years was 40%.
Conclusions: Patients with MCC treated with RTx
alone experience a high likelihood of obtaining
in-field disease control. Doses of 5055 Gy in 2025
fractions are recommended but lower doses (25 Gy in
five fractions) are still effective. A minority will be
cured with many patients subsequently dying of systemic relapse.
Key words: lymph node, Merkel cell carcinoma,
radiotherapy.

Merkel cell carcinoma (MCC) is an uncommon, often

aggressive primary cutaneous neuroendocrine (small cell)
carcinoma originating from the basal epidermis and first
reported by Toker in 1972.1 Lesions frequently develop on
the sun-exposed skin (head and neck, and extremities) in
older, often immunosuppressed, white patients.2,3 There is
evidence that surgery to achieve negative margins (but
respecting form and function), in combination with adjuvant wide field radiotherapy (RTx), significantly improves
locoregional control and survival compared with surgery
alone.46
In a minority of patients the extent of disease at presentation may be technically inoperable or patients may be
medically unfit for surgery, or occasionally decline surgery.
The unique radio-responsiveness of MCC provides the clinician with the option of RTx alone with moderate RTx
doses in the range of 4560 Gy.7Following treatment many
patients will ultimately die from distant relapse or unrelated
comorbidity but 4060% will be cured and it should not be
assumed that inoperable patients treated with RTx alone
are incurable.710
We have previously documented 43 patients treated at the
departments of radiation oncology, Westmead Hospital and
Royal Brisbane and Mater hospitals, Brisbane, with RTx
alone.7 Since this publication other groups have similarly
reported excellent in-field control rates following RTx.810
The aims of this study were to update our experience at
Westmead Hospital of patients with inoperable MCC treated
with RTx and review the outcome as well as update the
current literature.

METHODS

Correspondence: Clinical Professor Michael J Veness,

Department of Radiation Oncology, Westmead Cancer Care Centre,
University of Sydney, Westmead Hospital, Westmead, Sydney, NSW
2145, Australia. Email: michael.veness@health.nsw.gov.au
Michael Veness, MMed, MD (UNSW), MD (USyd), FRANZCR. Julie
Howle, MSurg, FRACS, FACS.
Conflict of interest: none
Submitted 12 August 2014; accepted 15 September 2014.
2014 The Australasian College of Dermatologists

Between 1993 and 2013 patients with MCC treated with RTx
alone were identified from a prospective departmental
Abbreviations:
CT
MCC
PET
RTx

computed tomography
Merkel cell carcinoma
positron emission tomography
radiotherapy as treatment

M Veness and J Howle

computer database. Prior to 2001 patients data were collected retrospectively. Ethics committee approval was previously obtained. All patients had a histological diagnosis
consistent with MCC (CK20 positive, positive neuroendocrine markers, negative melanoma and lymphoma
markers) without evidence of distant metastases. Pretreatment investigations were variable but included computed
tomography (CT) scans of involved regions with or without
uninvolved regions and more recently CT/positron emission
tomography (PET) scans in select patients. Patients treated
in the relapse setting were also biopsy confirmed and investigated. Data on patients characteristics, clinical details,
tumour details, pathology and treatment were extracted
from a computer database and the radiation oncology
medical files. Most patients returned for regular follow up for
5 years. A small number of patients continued to follow up
with their local doctors and the relevant follow-up status was
obtained for most of these patients.

Statistical analysis
A descriptive analysis was performed reporting relevant
median values. Overall survival (OS) was calculated using
KaplanMeier survival curves and the logrank (Mantel
Cox) test was utilised to compare survival curves. Descriptive analysis and data collection was performed using SPSS
vers. 20 (SPSS, IBM, New York, USA).

RESULTS
Patients characteristics
The median age at diagnosis was 80 years (range 4596
years) in 18 (44%) women and 23 (56%) men. All but one
patient were white and six (15%) were immunosuppressed
(three transplant recipients and three chronic lymphocytic
leukaemia) (Table 1).
Most patients (24/41; 59%) were irradiated at initial presentation with the remainder (18/41; 44%) treated in the
relapse setting (Fig. 1a,b), most often a nodal relapse in a
previously untreated nodal basin. The median duration of
follow up was 39 months (range 392 months).
Many patients were considered to be either medically
inoperable as a consequence of comorbidity or technically
inoperable because of advanced disease, usually located in
the head and neck. A few patients, although potentially
operable, had low-volume disease considered curable with
RTx alone. No patient received chemotherapy in conjunction with RTx.

Location
The head and neck was the most frequently treated site
(28/41; 68%). Occult (without a documented primary) nodal
disease was present in five (12%) patients (four parotid or
cervical, or both; one groin).

Extent of disease at treatment

Most patients treated at initial presentation (21/24; 88%) had
nodal metastases irradiated, with 9/24 (38%) of these also
2014 The Australasian College of Dermatologists

with a concomitant macroscopic primary lesion present. The

remaining patients 10/24 with a primary lesion had these
excised but with close margins, many undergoing elective
RTx. All but one patient treated in the relapse setting underwent RTx for nodal or in-transit disease with only one patient
treated for an isolated 5-mm local relapse. The median
lesion size (primary or nodal) was 30 mm (range 5130 mm).

Radiotherapy details
The median dose to the primary site was 51 Gy (range,
2063 Gy) and the median nodal site dose was 50 Gy (range,
2064 Gy) usually given as a once-daily treatment. The
median fraction size was 2 Gy (range 25 Gy). A minority of
patients (n = 6) were treated with a hypofractionated dose
regime using larger fractions (35 Gy) and lower total doses
(2040 Gy).
The RTx technique most often employed, especially in the
head and neck, was a single large en bloc electron field
(912 MeV) with an overlying tissue-equivalent bolus
(12 cm) treating macroscopic disease with wide margins
(usually 34 cms). CT planning was often utilised to assess
the depth of disease and the selection of appropriate electron energy. Doses to nearby structures such as the ear,
orbit and spinal cord could also be calculated and limited, if
required. The prescribed dose was often to the 90% isodose.
Similarly, an orthovoltage (250300 kVp) photon field may
have also been utilised in select cases. If possible RTx fields
encompassed the primary lesion (when present), in-transit
tissues and regional nodes en bloc. Nodal regions were also
treated using opposed megavoltage photon fields, in some
circumstances.

Relapse
Only 6/41 (15%) experienced an in-field recurrence, most
(5/6) within a treated lymph node. A total of 21/41 (51%)
patients developed a relapse outside the irradiated field
during the follow-up period. Most out-of-field relapses were
to the visceral organs, with four patients experiencing an
out-of-field nodal relapse (three nodes, one in-transit). Only
three patients were successfully salvaged, two with a nodal
relapse and one with in-transit metastases. The median
time to first relapse was 4 months (range, 172 months).

Status at last follow up

At last follow up most patients (19/41; 46%) were alive and
disease free with 10% having died of unrelated causes. A
minority had either died of disease (12/41; 29%) or were
alive with disease (6/41; 15%).

Survival
OS at 2 and 5 years was 55 and 40%, respectively, with a
median OS of 29 months (Fig. 2). OS between patients
treated at the time of presentation or in the relapse setting
was not significantly different (P = 0.6) (Fig. 3).

No
No
No
No
Renal Tx

No

No
No
CLL

No
No
No

Renal Tx
No
No
No
No
CLL
No
Renal Tx
No
No

80 M
87 F
84 M
90 F
54 M

79 M

76 F
81 F
83 F

77 F
77 M
87 M

49 M
86 M
76 F
82 F
83 M
78 F
84 M
65 F
87 M
73 M

Relapse
Relapse
Relapse
Relapse
Relapse
Relapse
Relapse
Relapse
Relapse
Relapse

Relapse
Relapse
Relapse

Relapse
Relapse
Relapse

Relapse

Initial
Initial
Initial
Initial
Initial

Initial
Initial
Initial
Initial
Initial
Initial
Initial

Initial
Initial
Initial
Initial

Initial
Initial
Initial
Initial
Initial
Initial
Initial
Initial

Cervical nodes
Parotid nodes
Parotid + cervical nodes
Groin nodes
Primary and nodes
Cervical nodes
Cervical nodes
Parotid nodes + derm mets
Parotid + cervical nodes
Primary (excised)

Cervical nodes
Cervical nodes
In-transit mets

Cervical nodes
In-transit mets
Groin nodes

Axilla/dermal mets

Primary and nodes

Parotid nodes
Primary and nodes
Primary and nodes
Primary and nodes

Cervical nodes
Primary
Parotid nodes
Axillary nodes
Primary
Cervical nodes
Primary and nodes

Parotid nodes
Primary and nodes
Groin nodes
Primary and nodes

Groin nodes
Cervical nodes
Primary
Cervical nodes
Cervical nodes
Primary and nodes
Parotid and nodes
Groin nodes

Extent of gross disease

Upper limb below

elbow ( margin)
Cheek ( margin)
Lower neck ( margin)
Lower limb-below knee
( margin)
Cheek (+ margin)
Nose (+ margin)
Lower limb below
knee (+ margin)
Scalp (+ margin)
Scalp (excised)
Forehead
Lower leg (excised)
Forehead (+ margin)
Nose (excised)
Scalp (excised)
Temple (+ margin)
Ear
Upper back

Ear
Eyelid
Unknown primary
Lower limb, below knee
(biopsy only)
Cheek
Foot (biopsy only)
Unknown primary
Upper arm
Forehead (biopsy only)
Unknown primary
Right cheek (biopsy
only)
Trunk (biopsy only)
Cheek (excised)
Lower lip (excised)
Cheek (excised)
Scalp (biopsy only)

Calf
Unknown primary
Cheek
Cheek
Ear
Trunk (biopsy only)
Unknown primary
Calf

Primary site (at diagnosis)

N/A
N/A
N/A
N/A
N/A
N/A
N/A
50
40
N/A
N/A
55
45
45
30
N/A
30

30
30
50
40
35
10
30
25
20
60
35
35
30
50
30
5

55
55
50
30
60

55

50

70
25

60

40
50

60

50
N/A
65
45
60
20

RTx dose
Primary (Gy)

15

60
15
30
15
60

50
15
20
60
40
20
50

15
30
130
100

35
30
60
10
5
Unknown
30
30

Maximum
lesion size
(mm)

50
30
55
50
55
45
30
30
55

25
50
40

60
50
45

50

55
55
50
30
50

60
20
50
50
45

70

50
50
30
60

45
60
20
60
58

60
45

RTx dose
Nodes (Gy)

No
No
Yes (node)
No
No
No
No
No
No
No

Yes (node)
Yes (node)
No

No
No
No

No

No
No
Yes (node)
No
No

Yes (node)
No
No
No
No
No
No

No
No
No
No

No
No
No
No
No
Yes (primary)
No
No

In-field
recurrence

No
Distant
Regional out
of field
No
No
Regional out
of field
No
No
No
Distant
Distant
No
No
No
Distant
Distant

Distant
No
Distant
Distant
Regional out
of field
No

Distant
No
No
Distant
Distant
Distant
No

N/A
N/A
Distant
Distant

N/A
N/A
No
No
Distant
Distant
Distant
In-transit

Site of other
recurrence

negative; CLL, chronic lymphocytic leukaemia; derm, dermal metastases; FU, follow up; mets, metastases; N/A, not available; RTx, radiotherapy, Tx, transplant.

No
No
No
No
No
No
No

71 M
91 M
75 M
79 F
88 F
63 M
79 M

No
No
No
No

83 M
96 M
83 F
87 F

positive;

No
No
No
CLL
No
No
No
No

77 M
82 F
45 M
79 F
81 M
86 F
80 M
80 F

Immunosuppressed

Treatment
setting

Characteristics Merkel cell carcinoma patients treated with radiotherapy RTx alone

Age/sex

Table 1

N/A
10 months
4 months
3 months
19 months
15 months
2 months
N/A
3 months
5 months

7 months
4 months
4 months

N/A
6 months
N/A

N/A

3 months
N/A
3 months
7 months
2 months

8 months
N/A
N/A
14 months
4 months
72 months
N/A

N/A
N/A
3 months
6 months

N/A
N/A
N/A
N/A
9 months
3 months
11 months
1 month

Time to
recurrence

Status/duration (months)

Alive without disease; 92

Dead, other causes; 12
Alive with disease; 5
Dead from disease; 6
Alive with disease; 29
Alive without disease; 21
Dead, other causes; 24
Dead, other causes; 6
Dead from disease; 20
Dead from disease; 7

Dead, other causes 15

Alive without disease; 27
Alive without disease; 6

Alive without disease; 25

Alive with disease; 23
Alive without disease; 7

Alive without disease; 39

Dead from disease; 5

Alive without disease; 30
Dead from disease; 13
Alive with disease; 9
Alive without disease; 67

Dead from disease; 14

Alive without disease; 11
Alive without disease; 25
Dead from disease; 20
Dead from disease; 13
Dead from disease; 75
Alive without disease; 30

Alive without disease; 51

Alive without disease; 32
Alive without disease; 42
Alive without disease; 15
Dead from disease; 10
Alive with disease; 6
Alive with disease; 21
Alive without disease; 3
(lost to F/U)
Alive without disease; 7
Alive without disease; 28
Dead from disease; 6
Dead from disease; 8

Merkel cell carcinoma

3

2014 The Australasian College of Dermatologists

M Veness and J Howle

(a)

Survival (%)

100

50

20

40

60

Follow up (months)
Figure 2

Overall survival for all 41 patients.

(b)

Survival (%)

100
Logrank P = 0.6

50

20

40

60

Follow up (months)
Figure 3 Overall survival based on presentation with no statistical
difference on whether a patient was treated in the relapse setting or
at initial diagnosis.

DISCUSSION

Figure 1 (a) 72-year-old woman who had previously undergone

the excision of an 8-mm Merkel cell carcinoma from her right
temple. Excision margins were close and lymphovascular invasion
was present. The patient was not sent for an opinion on adjuvant
radiotherapy. (b) Nine months later she developed nodal relapse in
her ipsilateral upper neck and proceeded to definitive radiotherapy
(50 Gy in 20 fractions), experiencing complete clinical regression.
Ten months after completion of treatment she developed liver
metastases and died shortly after.

2014 The Australasian College of Dermatologists

The addition of adjuvant RTx to patients with MCC is generally accepted to be beneficial in improving locoregional
control and survival.11 Debate still remains on selecting
patients for adjuvant RTx but many institutions recommend
RTx to all but those with a very favourable pathology. The
documented benefits of adjuvant RTx also support the
potential role of RTx alone in inoperable patients, patients
who refuse surgery and patients with low-volume macroscopic disease. Patients fitting this definition comprised
20% of all patients referred to our institution.
In a 2003 French publication nine patients with stage 1
inoperable MCC underwent RTx alone (median dose
60 Gy).12 In this small study no patient experienced a
relapse, with a median follow up of 3 years. A more recent
French study documented only one of 25 (96% local control)
patients developing in-field relapse following treatment
with RTx alone (median dose 65Gy).8 With a median follow
up of 2.8 years 10 of 25 patients have died, none from MCC.
The mean tumour size was 2.2 cm and the study involved
only patients with primary MCC, without clinically involved

Merkel cell carcinoma

nodes. This excellent result, noting the absence of MCCrelated deaths, most likely reflects the absence of clinical
metastatic nodal involvement, which is a powerful predictor
of poor outcome.
In combination with data from our Brisbane colleagues,
we have previously documented an in-field control of 75%
in 43 inoperable patients, with most relapses arising in
distant visceral organs.7 With further follow up and the
addition of 22 extra patients we now document an 85%
in-field control rate. Colleagues from Royal Prince Alfred
Hospital, Sydney, similarly reported an 85% in-field control
rate for 26 patients treated with RTx alone, or RTx plus
chemotherapy (n = 8). At 2 years median follow up 77% of
the patients were alive and disease free, with five of six
patients relapsing at a distant site.8
In an Australian study of 88 MCC patients, all underwent
surgery, of whom 26 had macroscopic residual disease and
nine had microscopically positive resection margins.13 The
patients then received a combination of RTx (median dose
50 Gy) and synchronous chemotherapy. The authors
reported no significant difference in survival, or time to
locoregional failure, among the three groups (negative
margins, positive margins and macroscopic disease) with
most relapses occurring distantly. No patient with macroscopic residual disease experienced recurrence.
Researchers from the University of Washington reported
on 50 MCC patients with metastatic nodal (microscopic and
macroscopic) MCC treated with either RTx, or RTx and
surgery.10 In total, 24 patients had macroscopic nodal MCC
(median size 30 mm) and of these nine underwent RTx
alone versus 15 undergoing nodal surgery and adjuvant
RTx. At 2 years post-treatment there was no difference in
regional relapse-free survival (78 vs 73%; P = 0.8) or
disease-specific survival (P = 0.9). Not surprisingly 50% of
patients with macroscopic nodal MCC developed distant
metastases after completion of treatment. RTx details such
as the dose fractionation schedules used were not detailed
in this study.
RTx dose response data available for macroscopic MCC
are limited. However, a recent Australian study of 112 MCC
patients did document a dose response for patients with
macroscopic disease and recommended 55 Gy as a
minimum dose. In this study no patient with primary macroscopic disease developed in-field relapse at doses
> 56 Gy.14 Most studies using RTx alone report delivered
doses of between 4060 Gy, similar to our median dose of
50 Gy, and it is these relatively lower doses that improve the
tolerability of RTx in older patients. In a large Canadian
series of 57 patients treated with RTx the authors documented better relapse-free and cause-specific, survival with
RTx doses of 50Gy. In this study the results are similar to
our own, with a tumour control of 82% at 2 years and a
5-year OS of 39%.15 The authors recommended an RTx dose
of at 50 Gy in 2.5 Gy fractions for most patients with macroscopic MCC.
Of note, patients of very poor performance status may
receive lower dose fractionation schedules (e.g. 20 Gy in
five fractions or 30 Gy in 10 fractions) yet still achieved
durable tumour regression. When these doses are con-

verted to a biological equivalence dose of 2 Gy16 the equivalent total dose for most patients when converted to a 2 Gy
equivalent total dose equates to 3040 Gy in 2-Gy fractions.
Although
the
number
of
patients
receiving
hypofractionation was small (15%) these results suggest
that shorter palliative RTx schedules can still achieve a
worthwhile clinical response in this radio-responsive
malignancy. Whether the larger doses per fraction compensate for a lower total dose is unclear but may warrant future
investigation as an alternative approach to select patients of
poor performance status.
Our findings are consistent with the results of other institutions confirming excellent in-field disease control in the
setting of macroscopic, usually nodal MCC and the importance of RTx. Correctly planned and delivered RTx is highly
likely to eradicate locoregional disease with out-of-field
distant relapse the dominant pattern of relapse. Of note,
even in this poor prognosis group just under half of our
patients were alive and disease free at their last follow up,
with an OS survival at 5 years of 40%. Indeed, other groups
have reported OS rates of 5060% following RTx alone.8,10
Therefore, patients with inoperable MCC should not necessarily be considered incurable although many will ultimately succumb to distant relapse.

CONCLUSION
Patients considered medically or technically inoperable,
and of good performance status should be recommended
RTx with a dose of 5055 Gy in 2025 daily fractions with
wide fields encompassing macroscopic disease with a high
likelihood of achieving locoregional control. Lower dose/
fractionation schedules (e.g. 25 Gy in five fractions) may be
considered in patients of poor performance status to
improve their quality of life and potentially eradicate lowvolume disease.

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