Australasian Journal of Dermatology
Australasian Journal of Dermatology
Australasian Journal of Dermatology
doi: 10.1111/ajd.12263
ORIGINAL RESEARCH
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.
METHODS
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
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).
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).
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
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
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
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)
(a)
Survival (%)
100
50
20
40
60
Follow up (months)
Figure 2
(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
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
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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