Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy without Radical Surgical Excision

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O R I G I N AL A R T I C L E M E L A N O MA S

Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy

without Radical Surgical Excision

Chris Harrington, MbChB1 and Winkle Kwan2

1Department 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 loca-

tion or patient comorbidity. Clinical impression suggeststhat radiation treatment achieves good control of macro-

scopic 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 rad-

ical surgery.

Results. Fifty-seven patients received definitive radio-

therapy 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). AmericanJoint 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 multi-

variate 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

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 immune-

suppressed patients.1 Involved regional nodes are detect-

able 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 histologi-

cally clear margins.

4

Wide excision is commonlyrecommended 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 morelimited 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

Society of Surgical Oncology 2014

First Received: 22 January 2014;

Published Online: 8 July 2014

C. Harrington, MbChB

e-mail: [email protected]

Ann Surg Oncol (2014) 21:34013405

DOI 10.1245/s10434-014-3757-8


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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

The BCCA is the only provider of RT in the province ofBritish 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 tomogra-

phy (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 log-

rank 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,

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

(84.5 months for those alive at last follow-up). Table1

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.

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 (%)]

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) 11 (19)

III (any T, N1 M0) 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)

AJCCAmerican Joint Committee on Cancer

3402 C. Harrington, W. Kwan


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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

(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, can-

cer-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.

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 radio-

therapy 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

0

0.0

0.2

0.4

0.6

0.8

1.0 Survival Function

Censored

50 100 150

Time (months)

Local Recurrence Free Survival After Definitive

Irradiation of Primary Tumour

Proportionwithoutlocalrecurrence

200 250

FIG. 1 Local recurrence-free survival after radical irradiation of the

primary tumor

0

0.0

0.2

0.4

0.6

0.8

1.0 Survival Function

Censored

50 100

Time (months)

Cancer Specific Survival

ProportionSurviving

150 200 250

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

received radical irradiation

TABLE 2 Comparison of patients treated with radical RT versus

radical surgery

Radical RT Radical surgery

N 57 122

Male (%) 65 49

Median age (years) 75 74

Stage 1 (%) 23 59Stage 2 (%) 19 33.6

Stage 3 (%) 58 7.4

Local relapse (%) 11 8.2

Nodal relapse (%) 21 33

5-year relapse-free survival (%) 57 62

5-year cancer-specific survival (%) 68 77

5-year overall survival (%) 39 49

RTradiation treatment

Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy 3403


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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 RTin MCC. In keepingwith 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 reportsin the literature (Table3).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 cos-

metic 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 sur-

vival. Nevertheless, local and regional controls were

similar, confirming our clinical impression that radiother-

apy 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, cur-

rent 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

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

Author Year N Dose (Gy) Stage Infield control (%)a Survival (%)b

12 3

Elliot12 1981 1 38 NA NA 100 0

Pacella et al.13 1988 19 3650 1 18 95 2-year OS 63

Pilotti et al.14 1988 3 NA NA NA 100 100

Ashby et al.15 1989 2 3945 2 0 100 100

Morrison et al.16 1990 5 NA 5 0 100 0

Hasle17 1991 1 40 1 0 100 0

Meeuwissen et al.8 1995 8 4560 1 7 50 25

Suntharalingam et al.18 1995 2 7077.5 2 0 50 50

Poulsen et al.19 2003 15 50 median NA 1415 71 3-year OS 45

Mortier et al.20 2003 9 60 9 0 100 67

Koh and Veness21 2009 8 50 median 1 7 87.5 12.5

Fang et al.22 2010 9 NA 0 9 5-year NRFS 78 2-year OS 63

Foote et al.23 2010 13 NA 0 13 NA 5-year OS 51

Pape et al.24 2010 25 65 median 25 0 92 60

Veness et al.

25

2010 43 51 median 10 33 75 5-year OS 37Fields et al.26 2011 22 C50 1 21 NA NA

Ghadjar et al.7 2011 13 60 median 8 5 5-year LRFS 82 NA

Kukko et al.27 2011 6 NA NA NA 67 NA

Lok et al.28 2011 10 6070 5 5 100 NA

Mendenhall et al.29 2012 6 60 median 2 2 67 NA

Sundaresan et al.30 2012 16 50 median NA 1012 85 NA

Santamaria-Barria et al.31 2013 12 NA 5 7 83 NA

NA data not available, OSoverall survival, NRFSnodal relapse-free survival, LRFSlocal relapse-free survivala Percent without recurrence at treated site at study end, unless otherwise statedb Proportion alive at study end unless otherwise stated

3404 C. Harrington, W. Kwan


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more. A similar improvement in infield controlwith 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

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, espe-

cially 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 irra-

diating the whole nodal region should be considered when

treating involved nodes.

CONFLICTS OF INTEREST None declared.

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Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy 3405

Outcomes of Merkel Cell Carcinoma Treated with Radiotherapy without Radical Surgical Excision

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