australasian journal of dermatology

8/10/2019 Australasian Journal of Dermatology

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ORIGINAL RESEARCH

Radiotherapy alone in patients with Merkel cellcarcinoma: 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

ABSTRACT

Objectives: To review the role of radiotherapy as

treatment (RTx) alone in patients with Merkel cellcarcinoma (MCC).

Methods: Data on 41 patients with MCC treatedwith RTx alone between 1993 and 2013 at Westmead

Hospital, Sydney, were reviewed and analysed.

Results: The patients median age was 80 (range4596 years) among 18 (44%) women and 23 (56%)

men. All but one patient were white and six (15%)

were immunosuppressed. Most (59%) were irradi-

ated 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 fre-

quently treated site (63%). The median lesion size

was 30 mm (range 5130 mm). The in-field controlrate was 85%. Most out-of-field relapses were to vis-

ceral organs. Overall survival at 5 years was 40%.

Conclusions: Patients with MCC treated with RTxalone 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 sys-

temic relapse.

Key words: lymph node, Merkel cell carcinoma,

radiotherapy.

INTRODUCTION

Merkel cell carcinoma (MCC) is an uncommon, often

aggressive primary cutaneous neuroendocrine (small cell)

carcinoma originating from the basal epidermis and firstreported 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 adju-

vant 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 presen-

tation may be technically inoperable or patients may be

medically unfit for surgery, or occasionally decline surgery.

The unique radio-responsiveness of MCC provides the cli-

nician with the option of RTx alone with moderate RTx

doses in the range of 4560 Gy.7Following treatment manypatients 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

Between 1993 and 2013 patients with MCC treated with RTx

alone were identified from a prospective departmentalCorrespondence: Clinical Professor Michael J Veness,

Department of Radiation Oncology, Westmead Cancer Care Centre,University of Sydney, Westmead Hospital, Westmead, Sydney, NSW2145, Australia. Email: [email protected]

Michael Veness, MMed, MD (UNSW), MD (USyd), FRANZCR. JulieHowle, MSurg, FRACS, FACS.

Conflict of interest: noneSubmitted 12 August 2014; accepted 15 September 2014.

Abbreviations:

CT computed tomographyMCC Merkel cell carcinomaPET positron emission tomographyRTx radiotherapy as treatment

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Australasian Journal of Dermatology(2014) , doi: 10.1111/ajd.12263

2014 The Australasian College of Dermatologists
mailto:[email protected]:[email protected]


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computer database. Prior to 2001 patients data were col-

lected retrospectively. Ethics committee approval was previ-

ously obtained. All patients had a histological diagnosis

consistent with MCC (CK20 positive, positive neuro-

endocrine markers, negative melanoma and lymphoma

markers) without evidence of distant metastases. Pretreat-

ment investigations were variable but included computed

tomography (CT) scans of involved regions with or withoutuninvolved regions and more recently CT/positron emission

tomography (PET) scans in select patients. Patients treated

in the relapse setting were also biopsy confirmed and inves-

tigated. Data on patients characteristics, clinical details,

tumour details, pathology and treatment were extracted

from a computer database and the radiation oncology

medicalfiles.Most patients returned forregular 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 relevantmedian values. Overall survival (OS) was calculated using

KaplanMeier survival curves and the logrank (Mantel

Cox) test was utilised to compare survival curves. Descrip-

tive 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 lymphocyticleukaemia) (Table 1).

Most patients (24/41; 59%) were irradiated at initial pres-

entation 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 conjunc-

tion 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 initialpresentation (21/24; 88%) had

nodal metastases irradiated, with 9/24 (38%) of these also

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 under-

went RTx for nodal or in-transit disease with only one patient

treated for an isolated 5-mm local relapse. The median

lesionsize (primary or nodal) was30 mm (range5130 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 elec-

tron 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 anddisease 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).

2 M Veness and J Howle



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DISCUSSION

The addition of adjuvant RTx to patients with MCC is gen-

erally 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 macro-

scopic 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

(a)

(b)

Figure 1 (a) 72-year-old woman who had previously undergonethe excision of an 8-mm Merkel cell carcinoma from her righttemple. Excision margins were close and lymphovascular invasion

was present. The patient was not sent for an opinion on adjuvantradiotherapy. (b) Nine months later she developed nodal relapse inher 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 livermetastases and died shortly after.

100

50

00 20 40

Follow up (months)

Survival(%)

60

Figure 2 Overall survival for all 41 patients.

100

50

00 20

Logrank P= 0.6

40

Follow up (months)

Survival(%)

60

Figure 3 Overall survival based on presentation with no statisticaldifference on whether a patient was treated in the relapse setting orat initial diagnosis.




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nodes. This excellent result, noting the absence of MCC-

related 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 theaddition 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 tolocoregional failure, among the three groups (negative

margins, positive margins and macroscopic disease) with

most relapses occurring distantly. No patient with macro-

scopic 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 distantmetastases 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 mac-

roscopic 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 docu-

mented better relapse-free and cause-specific, survival with

RTx doses of50Gy. 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 mac-

roscopic 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 equiva-

lent 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 compen-sate 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 insti-

tutions confirming excellent in-field disease control in the

setting of macroscopic, usually nodal MCC and the impor-

tance 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 neces-

sarily be considered incurable although many will ulti-

mately 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 low-

volume disease.

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3. Veness MJ, Palme CE, Morgan GJ. Merkel cell carcinoma: areview of management. Curr. Opin. Otolaryngol. Head NeckSurg.2008; 16: 1704.

4. Howle JR, Hughes TM, Gebski Vet al. Merkel cell carcinoma:

an Australian perspective and the importance of addressingthe regional lymph nodes in clinically node-negative patients.

J. Am. Acad. Dermatol.2012;67: 3340.5. Garneski KM, Nghiem P. Merkel cell carcinoma adjuvant

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8. Sundaresan P, Hruby G, Hamilton A et al. Definitive radio-therapy or chemoradiotherapy in the treatment of Merkel cellcarcinoma. Clin. Oncol. 2012; 24: e1316.

9. Pape E, Rezvoy N, Penal Net al. Radiotherapy alone for Merkelcell carcinoma: a comparative and retrospective study of 25patients.J. Am. Acad. Dermatol.2011;65: 98390.

10. Fang LC, Lemos B, Douglas Jet al. Radiation monotherapy asregional treatment for lymph node-positive Merkel cell carci-

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12. Mortier L, Mirabel X, Fournier Cet al. Radiotherapy alone forprimary Merkel cell carcinoma. Arch. Dermatol. 2003; 139:158790.

13. Finnigan R, Hruby G, Wratten C et al. The impact ofpreradiation residual disease volume on time to locoregionalfailure in cutaneous Merkel cell carcinoma A TROGsubstudy.Int. J. Radiat. Oncol. Biol. Phys. 2013; 86: 915.

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