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Ann Surg Oncol (2014) 21:34013405

DOI 10.1245/s10434-014-3757-8

ORIGINAL ARTICLE MELANOMAS

Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy


without Radical Surgical Excision
Chris Harrington, MbChB1 and Winkle Kwan2
Department of Oncology, Christchurch Hospital, Christchurch, New Zealand; 2Department of Radiation Oncology, British
Columbia Cancer Agency, Vancouver, BC, Canada

ABSTRACT
Background. Achieving clear surgical margins in Merkel
cell carcinoma (MCC) can be difficult due to tumor location or patient comorbidity. Clinical impression suggests
that radiation treatment achieves good control of macroscopic disease.
Methods. A retrospective chart review was undertaken of
all patients with pathological evidence of MCC and treated
with curative intent at the BC Cancer Agency between
1979 and 2007. This is a report on the outcomes of those
with gross disease treated with radiotherapy, without radical surgery.
Results. Fifty-seven patients received definitive radiotherapy to the primary and/or nodal disease. Median age
was 75 years and median follow-up was 34 months
(84.5 months for those alive at last follow-up). American
Joint Committee on Cancer (AJCC) stage distribution was
23, 19, and 58 % for stages I, II, and III, respectively.
Tumor control at sites treated for macroscopic disease was
88 % at 12 months and 82 % at 2 years, and 5-year local
relapse-free survival (RFS) was 90 %. Five-year RFS,
cancer-specific survival (CSS), and overall survival were
57, 68, and 39 %, respectively. On univariate and multivariate analyses, only male sex was associated with a worse
RFS, and a radiotherapy dose [50 Gy was associated with
a better CSS.
Limitations. The retrospective nature of the study and
small sample size limit the strength of the conclusions.
Conclusions. Radical radiotherapy is effective in the
curative treatment of MCC, especially in patients who

Society of Surgical Oncology 2014


First Received: 22 January 2014;
Published Online: 8 July 2014
C. Harrington, MbChB
e-mail: chris.harrington@cdhb.health.nz

would tolerate wide surgical excision poorly, or where it


would cause significant cosmetic or functional deficits.

Merkel cell carcinoma (MCC) is a rare neuroendocrine


skin tumor predominantly affecting elderly and immunesuppressed patients.1 Involved regional nodes are detectable clinically in approximately 25 %, and nodal
involvement rises to about 50 % if pathologic staging is
performed routinely.2 Metastatic disease is present in less
than 10 % of patients at diagnosis, but about one-third of
patients eventually die from distant metastatic MCC.2,3
Surgery is the usual initial therapy for primary MCC
tumors, and the National Comprehensive Cancer Network
guideline from 2009 recommends excision with histologically clear margins.4 Wide excision is commonly
recommended with margins of at least 1 cm, and 2 cm or
more has been suggested as the optimal radial margin.3,5,6
However, wide local excision in this group of patients
frequently result in functional or cosmetic defects because
head and neck sites are the most common presenting
location for the tumor. In addition, MCCs tend to present in
the elderly, and this group of patients frequently have
numerous comorbidities, making radical surgery difficult.
The role of postoperative radiation treatment (RT) is
debated. It is supported in some series,7,8 and may be given
in the setting of gross residual disease.
At the BC Cancer Agency (BCCA), a policy of more
limited surgery followed by RT has been liberally used in
patients who cannot tolerate wide local excision, with the
clinical impression of excellent local control. Yet, to date,
published series of the use of RT in the presence of gross
disease in MCC have contained relatively small numbers,
reporting an infield control in the 7080 % range. This is a
review of the treatment outcomes of curative intent
radiotherapy to macroscopic MCC (radical radiation)
defined by the use of radiation in patients with gross

3402

residual disease or after excision with grossly positive


marginscomparing the strategy with the more traditional
approach of wide local excision with or without adjuvant
radiotherapy.
METHODS

C. Harrington, W. Kwan
TABLE 1 Baseline characteristics
N

57

Median age [years (range)]

75 (3694)

Male/female (%)

54/46

Median tumor size [mm (range)]

15 (4104)

T stage [n (%)]

The BCCA is the only provider of RT in the province of


British Columbia. The medical records of MCC patients
referred to the BCCA in the 28-year period 19792007
were reviewed. Eligible patients had pathological evidence
of MCC and received treatment with curative intent.
Patients who were treated with radical radiation after a
biopsy or an attempted resection with grossly positive
surgical margins were identified and analyzed for disease
control (local relapse, nodal relapse, relapse-free survival
[RFS] and cause-specific survival [CSS]). They were
compared with the remaining patients who were treated
more traditionally with wide surgical excision with or
without RT.
In this report, radical radiation was defined as RT of
macroscopic tumor (after biopsy or attempted excision
with macroscopic residual disease). Adjuvant radiation was
defined as radiotherapy applied to the surgical bed after a
minimum of gross total excision (but including patients
with microscopic positive margins).
The 2010 American Joint Committee on Cancer (AJCC)
staging system was used.9 There was no institutional policy
on staging investigations for MCC during the study period,
and imaging was arranged at the discretion of the treating
physicians. It is likely that the use of computed tomography (CT) scans increased during the study period. To allow
comparison between different RT schedules, reported
doses have been converted to the equivalent dose in 2 Gy
fractions (EQD2) using a/b of 10 for tumor and relative
biological effectiveness of 1.2 for orthovoltage.
Survival data were estimated using the KaplanMeier
method and statistical significance assessed with the logrank test. Multivariate analysis was performed using Cox
regression. Significance level was drawn at a p-value of
\0.05.
RESULTS
Patient and Treatment Details
Between 1979 and 2007, 179 patients with stage IIII
MCC underwent treatment of MCC with curative intent at
the BCCA . Fifty-seven of these had gross residual disease
treated with radiotherapy to the primary site and/or nodal
region. The median age of these 57 patients was 75 years.
AJCC stage distribution was 23, 19, and 58 % for stages I,

T0

9 (16)

T1 (tumor B 2 cm)

19 (33)

T2 (tumor [ 2 cm but B 5 cm)

14 (25)

T34 (T3: [ 5 cm; T4: deep invasion)

15 (26)

Stage group (AJCC 2010) [n (%)]


I (T1N0M0)

13 (23)

II (T2/3N0M0)
III (any T, N1 M0)

11 (19)
33 (58)

Primary site [n (%)]


Head and neck

33 (58)

Upper limb

6 (11)

Trunk and lower limb

10 (17)

No primary

9 (16)

Comorbidity [n (%)]
Previous non-melanoma skin cancer

14 (25)

Previous melanoma

3 (5.3)

Previous non-skin cancer

15 (26)

Chronic lymphatic leukemia

4 (7)

Cardiovascular disease

11 (19)

Neurodegenerative disease

3 (5.3)

Renal transplant

2 (3.5)

AJCC American Joint Committee on Cancer

II, and III, respectively. Median follow-up was 34 months


(84.5 months for those alive at last follow-up). Table 1
shows the baseline characteristics of these 57 patients.
Of the 57 patients treated with radical radiation, 42
received radiation to the primary tumor, and 33 to involved
lymph nodes (18 had RT to both the primary and nodes).
Nine patients presented with clinically involved nodes
without an identified primary.
Thirty-seven patients had a biopsy only, and five had
gross residual tumor after an excision attempt. None of the
patients had a nodal dissection, and nodal involvement was
confirmed by biopsy in 17 patients. Positron emission
tomography (PET) staging and sentinel node biopsy were
generally not done in British Columbia during the era when
these patients were treated. Only one of the 57 patients had
a sentinel node biopsy.
Median EQD2 was 52.1 Gy (range 32.566 Gy). EQD2
was C60 Gy in 17 % and C50 Gy in 73 %. Field margins
were generally C3 cm around the lesion and when smaller
margins were used this was usually at a head and neck site.
Three patients (5.3 %) received adjuvant chemotherapy.

Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy

Proportion without local recurrence

Local Recurrence Free Survival After Definitive


Irradiation of Primary Tumour

3403
TABLE 2 Comparison of patients treated with radical RT versus
radical surgery

Survival Function
Censored

1.0

0.8

0.6

0.4

0.2

0.0
0

50

100

150

200

250

Radical RT

Radical surgery

57

122

Male (%)

65

49

Median age (years)

75

74

Stage 1 (%)

23

59

Stage 2 (%)

19

33.6

Stage 3 (%)

58

7.4

Local relapse (%)


Nodal relapse (%)

11
21

8.2
33

5-year relapse-free survival (%)

57

62

5-year cancer-specific survival (%)

68

77

5-year overall survival (%)

39

49

Time (months)

RT radiation treatment
FIG. 1 Local recurrence-free survival after radical irradiation of the
primary tumor

Cancer Specific Survival


Survival Function
Censored

1.0

Proportion Surviving

0.8

0.6

0.4

0.2

0.0
0

50

100

150

200

(p = 0.046), compared with less than 50 Gy. Local relapse


occurred in 23 % (3/13) after EQD2 \50 Gy versus 4.2 %
(1/24) after C50 Gy (p = 0.012).
Seventeen patients (30 %) died from MCC and 25
(44 %) from other causes. Eight-three percent of relapses
occurred within 2 years of diagnosis. Five-year RFS, cancer-specific survival and overall survival (OS) were 57, 68
and 39 %, respectively. Ten-year cancer-specific survival
was 65 % (Fig. 2).
Eight patients received salvage therapy with curative
intent. Two patients with infield relapses were treated
surgically, and the remaining patients (four out of field, two
field edge) received RT. Three remain alive, two died from
MCC, and three from other causes.

250

Time (months)

FIG. 2 Merkel cell cancer-specific survival for patients who


received radical irradiation

Cancer Control
Tumor control at sites treated for macroscopic disease
was 88 % at 12 months and 82 % at 2 years. Four patients
developed local recurrence as first site of failure after
radical RT to the primary tumor (11 %). Local RFS was
90 % at 5 years (Fig. 1).
After RT to grossly involved nodes, 7 of the 33 patients
(21 %) recurred first at nodal sites. Three recurred at nodal
sites outside the original field and four patients (12 %)
relapsed within (two) or at the edge (two) of the irradiated
field. Five-year nodal RFS amongst those treated with
radical nodal RT was 75 %.
Treatment to EQD2 of C50 Gy was associated with
improved RFS (p = 0.01) and cancer-specific survival

Factors Associated with Worse Disease Control


Age, sex, T stage, nodal status, primary site, surgery,
radiation EQD2, and radiation modality were assessed for
effects on CSS and RFS on univariate analysis. Male sex
and an EQD2 \50 Gy were associated with a poorer CSS
(p = 0.037 and 0.042, respectively). Males also had a
poorer RFS (p = 0.015). Multivariate analyses showed that
the male sex is the only factor significant for poorer RFS
(p = 0.018), whereas both the male sex and lower radiotherapy dose were associated with a trend towards poorer
CSS (p = 0.054 and 0.06, respectively).
Comparison with the Local Cohort Treated with
Radical Surgery (with or without Radiation Treatment)
When the cohort treated with radical radiation was
compared with the 122 patients treated with at least gross
total resection of macroscopic disease, it was noted that the
former group had more males and higher stage (especially

3404

C. Harrington, W. Kwan

TABLE 3 Published reports of radiotherapy to macroscopic merkel cell carcinoma with outcome data specific to these patients
Author

Year

Dose (Gy)

Stage
12

Infield control (%)a

Survival (%)b

Elliot12

1981

38

NA

NA

100

Pacella et al.13

1988

19

3650

18

95

2-year OS 63

Pilotti et al.14

1988

NA

NA

NA

100

100

Ashby et al.15

1989

3945

100

100

Morrison et al.16

1990

NA

100

Hasle17

1991

40

100

Meeuwissen et al.8
Suntharalingam et al.18

1995
1995

8
2

4560
7077.5

1
2

7
0

50
50

25
50

Poulsen et al.19

2003

15

50 median

NA

1415

71

3-year OS 45

Mortier et al.20

2003

60

100

67

Koh and Veness21

2009

50 median

87.5

12.5

Fang et al.22

2010

NA

5-year NRFS 78

2-year OS 63

Foote et al.23

2010

13

NA

13

NA

5-year OS 51

Pape et al.

2010

25

65 median

25

92

60

Veness et al.25

2010

43

51 median

10

33

75

5-year OS 37

Fields et al.26

2011

22

C50

21

NA

NA

Ghadjar et al.7

2011

13

60 median

5-year LRFS 82

NA

Kukko et al.27

2011

NA

NA

NA

67

NA

100

NA
NA

24

Lok et al.28

2011

10

6070

29

2012

60 median

67

Sundaresan et al.30

2012

16

50 median

NA

1012

85

NA

Santamaria-Barria et al.31

2013

12

NA

83

NA

Mendenhall et al.

NA data not available, OS overall survival, NRFS nodal relapse-free survival, LRFS local relapse-free survival
a

Percent without recurrence at treated site at study end, unless otherwise stated

Proportion alive at study end unless otherwise stated

stage 3 disease) [Table 2]. Yet, the local and nodal relapse
rates are comparable (11 vs. 8.2 % local relapse; 21 vs.
33 % nodal relapse). The 5-year OS and CSS of the
patients who had radical radiation are lower, consistent
with their more advanced disease at presentation.
DISCUSSION
The current series is one of the largest examining the role
of radical RT in MCC. In keeping with other series,10,11 these
patients are elderly and had a relatively high prevalence of
comorbidities, including immunosuppressive states and
previous treatments for other cancers. We found that control
at sites treated with radical radiation without aggressive
surgery was high for both primary and nodal disease, in
keeping with previous reports in the literature (Table 3).1231
With local relapse rate only at 11 % at 5 years, radical
RT to the primary tumor can be considered an alternative
to surgery, especially when the required operation would
be extensive, or likely to have a poor functional or cosmetic result.

Not surprisingly, patients treated with radical RT were


very different from patients treated in our institution with
radical surgery. The prognoses of the two groups are
probably dominated by the stage at diagnosis, with patients
treated with radical RT having a much higher proportion of
stage 3 patients and therefore a poorer cause-specific survival. Nevertheless, local and regional controls were
similar, confirming our clinical impression that radiotherapy employed in the presence of gross disease is effective
treatment for MCCs.
Infield or field edge recurrence after radical nodal RT
occurred in 12 %. While this is not excessively high, current radiotherapy techniques allow treatment to a bigger
volume with lower toxicity, and we certainly recommend
generous field margins, treating the entire nodal basin,
when radical radiotherapy is used for treating gross disease
within a nodal region.
MCC is often referred to as a radiosensitive tumor and
its radiation response is often characterized by rapid
shrinkage. Our data suggest an intermediate sensitivity,
with better control of gross disease after EQD2 of 50 Gy or

Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy

more. A similar improvement in infield control with radical


RT to 50 Gy or more was found by Foote et al.23 and Pape
et al.24, who found few infield relapses after a minimum
dose of 50 Gy. In the BCCA, we follow this principal by
using a minimum dose of at least 5052.5 Gy (in 2.5 Gy
fractions) on gross disease. For bulkier disease, dose
escalation to 60 Gy in 2.5 Gy fractions is used

14.

15.

16.

CONCLUSION
The current series adds to the literature supporting
radiotherapy to gross residual disease as an option for
management of local and regional disease in MCC, especially in situations where extensive surgery is not favored.
A radiotherapy dose of 50 Gy (in 2.5 Gy fractions) or more
is recommended. Field edge recurrences suggest that irradiating the whole nodal region should be considered when
treating involved nodes.
CONFLICTS OF INTEREST

3405

None declared.

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