SURGICAL ONCOLOGY

Outcomes of patients with metastatic cutaneous squamous cell

carcinoma to the axilla: a multicentre cohort study
Phillip F. Yang ,*† Michael J. Veness,‡§ Edward A. Cooper ,* Richard Fox,* Robert I. Smee,¶
Christopher Lehane,* Philip J. Crowe ,*† Julie R. Howle §∥ and Stephen R. Thompson †¶
*Department of Surgery, Prince of Wales Hospital, Sydney, New South Wales, Australia
†Prince of Wales Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, New South Wales, Australia
‡Department of Radiation Oncology, Westmead Hospital, Sydney, New South Wales, Australia
§Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
¶Department of Radiation Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia and
∥Department of Surgery, Westmead Hospital, Sydney, New South Wales, Australia

Key words Abstract

carcinoma, squamous cell, lymph node excision,
lymphatic metastasis, radiotherapy, adjuvant, skin
neoplasm.
Correspondence
Dr Stephen R. Thompson, Department of
Radiation Oncology, Prince of Wales Hospital,
Barker Street, Randwick, Sydney, NSW 2031,
Australia. Email: stephen.thompson1@health.nsw.
gov.au
P. F. Yang MBBS, MS, FRACS;
M. J. Veness MBBS, MMed, MD, FRANZCR;
E. A. Cooper BSc, MBBS, MS; R. Fox BSc,
MBChB; R. I. Smee MBBS, FRANZCR;
C. Lehane MBBS, MS, FRACS;
P. J. Crowe MBBS, DPhil, FRCSC, FRACS;
J. R. Howle MBBS, MS, FRACS;
S. R. Thompson MBBS, PhD, FRANZCR.
Accepted for publication 29 December 2020.
doi: 10.1111/ans.16584
Background: Metastatic cutaneous squamous cell carcinoma to the axilla is uncommon,
with limited data to guide management. We sought to assess the outcomes of patients with
this condition after surgery and radiotherapy.
Methods: A retrospective cohort study of patients treated at two Australian hospitals from
1994 through 2016 was performed.
Results: A total of 74 patients were identified, including 48 treated curatively with surgery-
plus-radiotherapy and 15 with surgery alone. Compared with patients treated with surgery
alone, a higher proportion of patients treated with surgery-plus-radiotherapy had lymph
nodes larger than 6 cm (53% versus 8%, P = 0.012) and multiple adverse histopathological
features (75% versus 47%, P = 0.04). The groups had similar 5-year disease-free survival
(45% versus 46%) and overall survival (51% versus 48%). Presence of multiple positive
lymph nodes was associated with reduced disease-free survival (hazard ratio 4.57, P = 0.01)
and overall survival (hazard ratio 3.53, P = 0.02). Regional recurrence was higher in
patients treated with surgery alone (38% versus 22%, P = 0.22) and patients with lymph
nodes larger than 6 cm (34% versus 10%, P = 0.03). All recurrences occurred within 2 years
following treatment.
Conclusion: Combined-modality therapy for metastatic cutaneous squamous cell carci-
noma to the axilla is recommended for high-risk patients, although outcomes remain mod-
est. The key period for recurrence is within 2 years following treatment.

Most keratinocyte cancers occur on the head and neck, followed

Introduction
Keratinocyte cancer, comprising basal cell carcinoma and cutane-
ous squamous cell carcinoma (cSCC), is the most common cancer
worldwide. In Australia, their age-standardized incidence rates were
884 and 387 per 100 000, respectively, at the time of the last
national survey in 2002, with rates higher in men than in women.1
Despite its lower incidence, cSCC accounts for the majority of
keratinocyte cancer mortality due to its metastatic potential.2 Even
though most cases can be cured with surgery, ablation or radiother-
apy, up to 5% of patients will develop regional or distant
metastases.3–7
by the upper limbs.1 The majority of outcome data on treatment of
cSCC with regional metastases come from studies of patients with
primary tumours located on the head and neck and metastases to
the parotid gland and/or cervical lymph nodes. The preferred treat-
ment for these patients is either surgery alone (i.e. excision of the
primary tumour with parotidectomy and/or neck dissection) or
surgery-plus-adjuvant radiotherapy, with recurrence rates that range
from 20% to 35% and 5-year disease-free survival (DFS) from 59%
to 83%.8 In contrast, there are limited data to guide the manage-
ment of patients with metastatic cSCC to the axilla, with only five
studies published in the past 15 years.9–13

ANZ J Surg 91 (2021) 878–884 © 2021 Royal Australasian College of Surgeons


Metastatic cSCC to the axilla
The aim of this study is to assess the outcomes of patients with
metastatic cSCC to the axilla treated with surgery and radiotherapy,
given the limited data in this area.
Methods
An observational study was conducted on all adult patients with
metastatic cSCC to the axilla treated at the Prince of Wales Hospital
and Westmead Hospital, the two principal referral hospitals in Syd-
ney, from 1994 through 2016. Patients were identified from each
institution’s Cancer Centre database. These prospectively
maintained databases contain limited information on patient demo-
graphics, treatment and outcomes. Additional patient, tumour and
treatment characteristics, as well as outcome data, were obtained by
retrospective review of Cancer Centre, hospital and specialists’
records in October 2018. All available data were analysed. Sample
sizes were not calculated. The outcomes of all patients who met the
inclusion criteria were reported, with a focus on patients who were
treated with curative intent with surgery-plus-radiotherapy or sur-
gery alone.
The study endpoints were DFS, overall survival (OS) and
regional and distant recurrence. DFS was measured from the date
of axillary surgery until regional or distant recurrence of disease or
death from any cause. OS was measured from the start of any treat-
ment until death from any cause. Regional recurrence was defined
as recurrence of disease within the ipsilateral axilla or supra-
clavicular fossa. Adverse histopathological features were defined as
the presence of positive margins, poor differentiation, extracapsular
extension, perineural invasion, lymphovascular invasion, invasion
of adjacent structures, metastases in multiple lymph nodes and
lymph nodes larger than 6 cm in greatest dimension. Where appli-
cable, non-standard radiotherapy dose fractionation was converted
to an equivalent dose in 2 Gy per fraction using the linear-quadratic
model.
Comparisons of continuous variables were performed with the
unpaired t-test and comparisons of proportions were performed
with Pearson’s chi-squared test or Fisher’s exact test, as appropri-
ate. Analyses of survival were carried out using the Kaplan–Meier
Table 1 Primary lesion and treatment characteristics of patients with
metastatic cutaneous squamous cell carcinoma to the axilla (n = 74)
No.
†
Location(s) of primary lesion(s)
Head and neck 11 (15%)
Trunk 19 (26%)
Upper limb 33 (45%)
Unknown 15 (20%)
Treatment modality
Surgery-plus-adjuvant radiotherapy 45 (61%)
Surgery alone 15 (20%)
Neoadjuvant radiotherapy-plus-surgery 3 (4%)
Definitive radiotherapy 2 (3%)
Palliative radiotherapy 9 (12%)
Surgery performed (n = 63)
Axillary dissection 59 (94%)
Other 4 (6%)
†
Some patients had multiple primary lesions.
© 2021 Royal Australasian College of Surgeons
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879
method. Hazard ratios (HRs) of treatment and prognostic variables
were determined with the Cox proportional hazards model and vari-
ables with a P-value of <0.30 in the univariate analysis were
entered into a multivariate analysis using SPSS version 26.0 (IBM
Corp., Armonk, NY, USA). Cumulative incidence of regional
recurrence was determined using the competing risk method, in
which death was considered the only competing risk. Differences
between groups were assessed with Gray’s test14 and predictors in
the univariate analysis were entered into a multivariate competing
risk analysis using a proportional subdistribution hazards model15
using R version 4.0.1 (R Core Team), as described by Scrucca
et al.16,17 Patients with missing data were not included in analyses
that required the missing variable. All tests were two-sided and sta-
tistical significance was set at P < 0.05. Ethics approval was
granted by the South Eastern Sydney Local Health District Ethics
Committee.
Results
Patients
A total of 74 consecutive patients were treated for metastatic cSCC
to the axilla. The median age was 75 (range 33–95) years and
52 (70%) were male. Characteristics of the patients’ primary lesions
and nodal treatment are presented in Table 1. There were no signifi-
cant differences in these characteristics between patients treated
with surgery-plus-radiotherapy and patients treated with surgery
alone.
Surgical and radiotherapy procedures
Of the 48 patients treated with surgery-plus-radiotherapy, 44 (92%)
underwent complete axillary dissection, three (6%) debulking and
one (2%) underwent forequarter amputation. Of the 15 patients
treated with surgery alone, all underwent axillary dissection. Histo-
pathological characteristics of the nodal disease are presented in
Table 2. Compared with patients treated with surgery alone, a
higher proportion of patients treated with surgery-plus-radiotherapy
had lymph nodes larger than 6 cm (53% versus 8%, χ 2 = 8.9,
df = 2, P = 0.012) and multiple adverse histopathological features
(75% versus 47%, χ 2 = 4.2, df = 1, P = 0.04).
Of the 48 patients treated with surgery-plus-radiotherapy, three
(6%) received neoadjuvant radiotherapy and 45 (94%) received
adjuvant radiotherapy, the latter commencing a median of 44 days
(interquartile range 38.5–54 days) after surgery (Table S1). The
median dose of radiotherapy was 50 Gy (range 30–66 Gy) in
25 fractions (range 6–33 fractions), with 12 (26%) patients receiv-
ing more than 50 Gy. Most patients were treated with conformal
techniques. Data on target volume were available only for
20 patients, of whom eight (40%) were treated to the axilla only
and 12 (60%) to both axilla and supraclavicular fossa. Three
patients were treated with neoadjuvant radiotherapy in order to
downstage their disease, as proceeding with surgery upfront would
likely have resulted in a positive margin. Data on treatment-related
complications were available only for one of the two study sites
(Table S2).
 14452197, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ans.16584 by Unsw Library, Wiley Online Library on [19/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
880 Yang et al.

Table 2 Histopathological findings of patients with metastatic cutaneous squamous cell carcinoma to the axilla who were treated with surgery

Surgery-plus-radiotherapy (n = 48) Surgery alone (n = 15) P-value

Margin status
R0 17 (44%) 3 (75%) 0.23
R1 or R2 22 (56%) 1 (25%)
Unknown 9 11
Histological differentiation
Well 7 (19%) 3 (23%) 0.34
Moderate 17 (46%) 3 (23%)
Poor 13 (35%) 7 (54%)
Unknown 11 2
Extracapsular extension
Yes 28 (72%) 6 (50%) 0.20
No 11 (28%) 6 (50%)
Unknown 9 3
Perineural invasion
Yes 4 (17%) 0 0.55
No 19 (83%) 7 (100%)
Unknown 25 8
Lymphovascular invasion
Yes 10 (31%) 1 (13%) 0.41
No 22 (69%) 7 (87%)
Unknown 16 7
Invading adjacent structures
Yes 11 (27%) 2 (14%) 0.48
No 30 (73%) 12 (86%)
Unknown 7 1
Number of positive lymph nodes
Single 18 (45%) 7 (47%) 0.92
Multiple 22 (55%) 8 (53%)
Unknown 8 0
Size of largest nodal deposit (cm)
≤3 9 (23%) 4 (31%)
3.1–5.9 10 (25%) 8 (62%) 0.012
≥6 21 (53%) 1 (8%)
Unknown 8 2
Total number of adverse features
One or more 43 (90%) 13 (87%) 0.67
Two or more 36 (75%) 7 (47%) 0.04
Three or more 28 (58%) 3 (20%) 0.01

Two patients were treated with definitive radiotherapy due to
being medically unfit for surgery or having inoperable disease. One
received 40 Gy in 15 fractions and the other 60 Gy in 30 fractions.
Both patients had a partial response. Nine patients were treated with
palliative radiotherapy, six of whom had distant metastases at the
time of diagnosis. They received a median dose of 32 Gy (range
10–55 Gy) in six fractions (range 2–25 fractions). Two (22%)
patients had a complete response and six (67%) had a partial
response.

Survival
Of the 48 patients treated with surgery-plus-radiotherapy, 23 (48%)
developed recurrent disease and 27 (56%) died. Of the 15 patients
treated with surgery alone, six (40%) developed recurrent disease
and eight (53%) died. The median follow-up time was 29.7 months
(range 0.4–162.7 months), with 34 (54%) patients followed up for
at least 2 years and 18 (29%) for at least 5 years.
There was no statistically significant difference in DFS between
the two groups (HR 1.18, 95% confidence interval (CI) 0.55–2.52,
P = 0.67), with a median DFS of 17 months (95% CI 0–73 months)
in the surgery-plus-radiotherapy group versus 13 months (95% CI
Fig 1. Disease-free survival of patients with metastatic cutaneous squa-
mous cell carcinoma to the axilla who were treated with curative intent 0–85 months) in the surgery-only group (Fig. 1). In the surgery-
with surgery-plus-radiotherapy ( ) or surgery alone ( ) (P = 0.67). plus-radiotherapy group, both the 2-year and 5-year DFS were

© 2021 Royal Australasian College of Surgeons


Metastatic cSCC to the axilla
Fig 2. Overall survival of patients with metastatic cutaneous squamous
cell carcinoma to the axilla who were treated with curative intent with
surgery-plus-radiotherapy ( ) or surgery alone ( ) (P = 0.55).
45%. In the surgery-only group, both the 2-year and 5-year DFS
were 46%. Combined DFS was 49% at both 2 and 5 years.
There was also no statistically significant difference in OS
between the two groups (HR 1.29, 95% CI 0.56–2.99, P = 0.55),
with a median OS of 66 months (95% CI 27–105 months) in the
surgery-plus-radiotherapy group versus 36 months (95% CI
0–98 months) in the surgery-only group (Fig. 2). In the surgery-
plus radiotherapy group, the 2- and 5-year OS were 68% and 51%,
respectively. In the surgery-only group, the 2- and 5-year OS were
67% and 48%, respectively. Combined OS was 68% at 2 years and
51% at 5 years.
Predictors of DFS and OS on univariate analysis are presented in
Table S3. On multivariate analysis, only the presence of multiple
positive lymph nodes was associated with reduced DFS (HR 4.57,
95% CI 1.39–15.0, P = 0.01) and OS (HR 3.53, 95% CI 1.18–
10.54, P = 0.02). Treatment with a radiotherapy dose greater than
50 Gy was not associated with a difference in survival.
Of the two patients treated with definitive radiotherapy, one was
alive with disease at last follow-up at 7 months and the other died
of disease after 8 months. Neither patients developed distant recur-
rence. Of the nine patients treated with palliative radiotherapy, there
were seven (78%) deaths after a median follow-up time of
seven months (range 2.6–122.3 months).
Regional recurrence
Of the 48 patients treated with surgery-plus-radiotherapy, 10 (21%)
developed regional recurrence, all within 12 months of starting
treatment. Of the 15 patients treated with surgery alone, five (33%)
developed regional recurrence, all within 9 months of starting treat-
ment (Fig. 3). The cumulative incidence of regional recurrence at
2 years was 22% in the surgery-plus-radiotherapy group and 38%
in the surgery-only group (P = 0.22). Predictors of regional recur-
rence on univariate analysis are presented in Table S3. On multivar-
iate analysis, only the presence of lymph nodes larger than 6 cm
was associated with increased risk of regional recurrence (34%
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881
Fig 3. Cumulative incidence of regional recurrence of patients with meta-
static cutaneous squamous cell carcinoma to the axilla who were treated
with curative intent with surgery-plus-radiotherapy ( ) or surgery alone
( ) (P = 0.22).
versus 10%, RR 4.49, 95% CI 1.13–17.91, P = 0.03). Treatment
with a radiotherapy dose greater than 50 Gy was not associated
with a difference in regional recurrence. Of the five patients treated
with surgery alone who developed regional recurrence, one was
treated with salvage surgery and radiotherapy and died after
33 months of an unrelated cause, and three were treated with pallia-
tive radiotherapy, of whom two died within 6 months with disease
and one was alive with disease at last follow-up at 2 months.
Details of the fifth patient were unknown, other than that the patient
died after 27 months with disease.
Distant recurrence
Of the 48 patients treated with surgery-plus-radiotherapy, four (8%)
developed both regional and distant recurrence and 12 (25%) devel-
oped distant recurrence alone, all within 23 months of starting treat-
ment. Of the 15 patients treated with surgery alone, two (13%)
developed both regional and distant recurrence and one (7%) devel-
oped distant recurrence alone, all within 13 months of starting treat-
ment. No predictors of distant recurrence were found (Table S3).
Discussion
Our study reports on the outcomes of 74 patients treated for meta-
static cSCC to the axilla, with a focus on 63 patients who were
treated with curative intent with surgery-plus-radiotherapy or sur-
gery alone. It represents the largest modern series of its type.
Patients treated with surgery-plus-radiotherapy had similar survival
compared with patients treated with surgery alone, even though a
higher proportion had adverse histopathological features. The
cumulative incidence of regional recurrence at 2 years was lower in
patients treated with surgery-plus-radiotherapy, although this was
not statistically significant. The presence of a lymph node larger
than 6 cm was a predictor of regional recurrence and the presence
of multiple positive lymph nodes was a predictor of reduced DFS
and OS. All recurrences occurred within 2 years of starting
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882 Yang et al.

Table 3 Recent studies of patients with metastatic cutaneous squamous cell carcinoma to the axilla or groin who were treated with curative intent surgery

Study Patients with Surgery (Neo)adjuvant treatment Median 5-year 5-year Recurrence (%)
nodal follow- overall disease-
metastasis up survival free
Axilla Groin Complete Other† Radiotherapy Chemotherapy (months) (%) survival Regional Overall
lymph (%)
node
dissection

Mullen et al.9 23‡ 23 Unknown Unknown 13 42 29 0 52

Goh et al.10 17§ 9 17 9 13 2 18.5 27
Beydoun et al.11 26 21 5 26 0 38.4 32 41 35 50
Wach et al.12 33 18 51 23 12 74 56 46
Pang et al.13 31 12 43 34 2 38 55 49 21 26
†
Includes subtotal lymph node dissection and lumpectomy.
‡
Total for axilla and groin.
§
Includes one patient with epitrochlear nodal metastasis only.

treatment. Only five other studies have been published in the past
15 years on the treatment of patients with metastatic cSCC to the
axilla or groin and their outcomes are summarized in Table 3.9–13
Our main findings are in keeping with these outcomes.
Patients in our study who were treated with radiotherapy in addi-
tion to surgery had a lower rate of regional recurrence, despite hav-
ing more adverse histopathological features. This additive effect of
radiotherapy on regional disease control is also seen in the study by
Pang et al.,13 in which 11% of patients treated with adjuvant radio-
therapy developed a regional recurrence compared with 44% of
patients treated with surgery alone. In both studies, the differences
were not statistically significant, likely due to small sample sizes
and selection bias, whereby radiotherapy may have been given to
patients with more biologically aggressive tumours. In larger stud-
ies of other cancers, adjuvant radiotherapy has been found to
improve locoregional control in patients at high risk of recurrence,
including nodal metastasis from cSCC of the head and neck18 and
from cutaneous melanoma.19 It is therefore reasonable to recom-
mend the use of adjuvant radiotherapy in patients with metastatic
cSCC to the axilla who have a high risk of recurrence, as reflected
in current guidelines.8,20
Our study highlights several features about the behaviour of met-
astatic cSCC and the type of surgery that should be performed. In
our study, all patients who developed regional recurrence did so
within 12 months of starting treatment and no distant recurrences
were observed after 2 years. Likewise, in the study by Pang et al.,13
all recurrences occurred within 21 months with the majority doing
so within 9 months, and in Wach et al.’s study,12 which had a
median follow-up time of 74 months, all recurrences occurred
within 3 years. This suggests that treatment failure tends to occur
early, not dissimilar to patterns found in metastatic cSCC of the
head and neck.18 The study by Beydoun et al.11 seems to be an out-
lier, with a median time to regional recurrence of 6.1 years in the
subset of patients who had surgery-plus-radiotherapy. At 5 years,
their regional recurrence rate was 35% compared with 22% in our
study, despite a greater proportion of our patients having more
adverse histopathological features. The reason for this difference is
unclear, as both studies used similar radiotherapy doses. One nota-
ble difference is that only 81% of patients in their study underwent
a complete axillary dissection compared with 94% of patients in
our study and all the patients in the studies by Pang et al. and Wach
et al. This supports the current recommendation that patients should
undergo a complete lymph node dissection whenever feasible.8,20
The existence of predictors of disease recurrence remains
unclear. No consistent set of predictors for either survival or
regional recurrence have emerged from the recent studies, including
our own. Despite the conflicting data, it is reasonable to presume
that a correlation may exist between the burden of nodal disease
and regional recurrence. In the melanoma literature, for example,
the number of positive lymph nodes is a predictor of both OS and
recurrence-free survival in patients with regional metastases.21 It is
likely that the relatively small sample sizes in our current study and
studies by previous groups have again led to type II errors.
Our study has several strengths and weaknesses. We sought to
reduce heterogeneity by limiting our study to patients with meta-
static cSCC to the axilla. For completeness, we presented outcome
data for patients treated with definitive and palliative radiotherapy.
Several weaknesses of our study relate to its retrospective nature.
Some clinical information, such as immunosuppression status,
level of lymph node dissection, number of nodes examined on his-
topathology and treatment-related complications, could not be
ascertained or were incomplete. In addition, information on why
patients did or did not receive adjuvant radiotherapy was not
available. If some did not receive radiotherapy because they were
not fit for treatment, this would lead to selection bias and affect
the calculated survival outcomes. Furthermore, the allocation of
radiotherapy treatment was not randomized, which introduces
selection bias and tempers any conclusions about the effect of
radiotherapy on recurrence and survival following surgery. How-
ever, given the current consensus on the use of adjuvant radiother-
apy, it is difficult to justify conducting a randomized trial. Finally,
even though this is the largest study of its type, the overall small
sample size likely led to type II errors, as previously discussed.
Larger studies are needed to determine the optimal dose of radio-
therapy, whether radiotherapy confers any benefits to patients with
low-risk histopathological features, and whether dosage should be
increased for patients with greater numbers of adverse histopatho-
logical features.

© 2021 Royal Australasian College of Surgeons


Metastatic cSCC to the axilla
The efficacy of systemic therapy for patients with advanced
forms of cSCC has been limited prior to the development of mod-
ern immune checkpoint inhibitors. Conventional cytotoxic chemo-
therapy is not beneficial in the adjuvant setting.8,20 In one phase III
trial comparing adjuvant radiotherapy with or without weekly car-
boplatin in patients with cSCC of the head and neck, the majority
of whom had high-risk nodal disease, no significant differences in
freedom from locoregional relapse, DFS and OS were found.22
Monoclonal antibodies23,24 and tyrosine kinase inhibitors25,26
targeting the epidermal growth factor receptor have demonstrated
only modest response rates. In contrast, immune checkpoint inhibi-
tors such as those targeting the programmed cell death-1 receptor
have shown promising results.27 In a phase II trial of cemiplimab
involving 78 patients with locally advanced cSCC not amenable to
surgery or radiotherapy, a partial or complete response was seen in
34 (44%) patients.28 Two phase III trials of adjuvant cemiplimab
(NCT03969004) and pembrolizumab (NCT03833167) immuno-
therapy are currently recruiting. The results of these studies will be
highly relevant because there is clearly a need for an effective sys-
temic adjuvant treatment given the high recurrence and mortality
rates demonstrated in the study.
Conclusion
This study contributes to the limited literature on the outcomes of
patients with metastatic cSCC to the axilla. It identifies several
prognostic factors associated with survival and disease recurrence.
Patients at high risk of recurrence should ideally be treated with
surgery and radiotherapy, although outcomes remain modest. The
role of radiotherapy in patients with low-risk histopathological fea-
tures is unclear, as we have not determined that these patients
derive no benefit from radiotherapy. Patterns of failure suggest the
majority of disease recurrences occur within 2 years following
treatment, making this an important period for follow up. Results of
phase III trials of adjuvant immunotherapy are eagerly awaited.
Conflicts of interest
None declared.
Author Contributions
Phillip Yang: Data curation; formal analysis; visualization;
writing-original draft; writing-review and editing. Michael Veness:
Conceptualization; investigation; writing-review and editing.
Edward Cooper: Investigation. Richard Fox: Investigation.
Robert Smee: Investigation. Christopher Lehane: Supervision;
writing-review and editing. Philip Crowe: Writing-review and
editing. Julie Howle: Writing-review and editing. Stephen
Thompson: Conceptualization; methodology; supervision; writing-
review and editing.
© 2021 Royal Australasian College of Surgeons
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883
References
1. Staples MP, Elwood M, Burton RC, Williams JL, Marks R, Giles GG.
Non-melanoma skin cancer in Australia: the 2002 national survey and
trends since 1985. Med. J. Aust. 2006; 184: 6–10.
2. Cancer Council Australia Keratinocyte Cancers Guideline Working
Party. Clinical practice guidelines for keratinocyte cancer. [Updated
7 Nov 2019; cited 17 Mar 2020.]; 2019. Available from URL: https://
wiki.cancer.org.au/australia/guidelines:keratinocyte_carcinoma
3. Joseph MG, Zulueta WP, Kennedy PJ. Squamous cell carcinoma of the
skin of the trunk and limbs: the incidence of metastases and their out-
come. ANZ J. Surg. 1992; 62: 697–701.
4. Czarnecki D, Staples M, Mar A, Giles G, Meehan C. Metastases from
squamous cell carcinoma of the skin in southern Australia. Dermatol-
ogy 1994; 189: 52–4.
5. Brantsch KD, Meisner C, Schonfisch B et al. Analysis of risk factors
determining prognosis of cutaneous squamous-cell carcinoma: a pro-
spective study. Lancet Oncol. 2008; 9: 713–20.
6. Schmults CD, Karia PS, Carter JB, Han J, Qureshi AA. Factors predic-
tive of recurrence and death from cutaneous squamous cell carcinoma:
a 10-year, single-institution cohort study. JAMA Dermatol. 2013;
149: 541–7.
7. Khan K, Mykula R, Kerstein R et al. A 5-year follow-up study of
633 cutaneous SCC excisions: rates of local recurrence and lymph node
metastasis. J. Plast. Reconstr. Aesthet. Surg. 2018; 71: 1153–8.
8. National Comprehensive Cancer Network. Squamous cell skin cancer
(version 2.2019). [Updated 2 Oct 2019; cited 2 Feb 2019.]; 2019.
Available from URL: https://www.nccn.org/professionals/physician_
gls/pdf/squamous.pdf
9. Mullen JT, Feng L, Xing Y et al. Invasive squamous cell carcinoma of
the skin: defining a high-risk group. Ann. Surg. Oncol. 2006;
13: 902–9.
10. Goh A, Howle J, Hughes M, Veness MJ. Managing patients with cuta-
neous squamous cell carcinoma metastatic to the axilla or groin lymph
nodes. Australas. J. Dermatol. 2010; 51: 113–7.
11. Beydoun N, Graham PH, Browne L. Metastatic cutaneous squamous
cell carcinoma to the axilla: a review of patient outcomes and implica-
tions for future practice. World J. Oncol. 2012; 3: 217–26.
12. Wach MM, van Beek E, Ayabe R et al. Metastatic squamous cell carci-
noma of known and unknown primary origin treated with axillary or
inguinal lymphadenectomy. Am. J. Surg. 2018; 216: 963–8.
13. Pang G, Look Hong NJ, Paull G et al. Squamous cell carcinoma with
regional metastasis to axilla or groin lymph nodes: a multicentre out-
come analysis. Ann. Surg. Oncol. 2019; 26: 4642–50.
14. Gray RJ. A class of K-sample tests for comparing the cumulative inci-
dence of a competing risk. Ann. Stat. 1988; 16: 1141–54.
15. Fine JP, Gray RJ. A proportional hazards model for the subdistribution
of a competing risk. J. Am. Stat. Assoc. 1999; 94: 496–509.
16. Scrucca L, Santucci A, Aversa F. Competing risk analysis using R:
an easy guide for clinicians. Bone Marrow Transplant. 2007;
40: 381–7.
17. Scrucca L, Santucci A, Aversa F. Regression modeling of competing
risk using R: an in depth guide for clinicians. Bone Marrow Transplant.
2010; 45: 1388–95.
18. Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant
radiotherapy in patients with cutaneous head and neck squamous cell
carcinoma metastatic to lymph nodes: combined treatment should be
considered best practice. Laryngoscope 2005; 115: 870–5.
19. Henderson MA, Burmeister BH, Ainslie J et al. Adjuvant lymph-node
field radiotherapy versus observation only in patients with melanoma at
high risk of further lymph-node field relapse after lymphadenectomy

884
(ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase
3, randomised controlled trial. Lancet Oncol. 2015; 16: 1049–60.
20. Stratigos AJ, Garbe C, Dessinioti C et al. European interdisciplinary
guideline on invasive squamous cell carcinoma of the skin: part 2. Treat-
ment. Eur. J. Cancer 2020; 128: 83–102.
21. White RR, Stanley WE, Johnson JL, Tyler DS, Seigler HF. Long-term
survival in 2,505 patients with melanoma with regional lymph node
metastasis. Ann. Surg. 2002; 235: 879–87.
22. Porceddu SV, Bressel M, Poulsen MG et al. Postoperative concurrent
chemoradiotherapy versus postoperative radiotherapy in high-risk cuta-
neous squamous cell carcinoma of the head and neck: the randomized
phase III TROG 05.01 trial. J. Clin. Oncol. 2018; 36: 1275–83.
23. Maubec E, Petrow P, Scheer-Senyarich I et al. Phase II study of
cetuximab as first-line single-drug therapy in patients with unresectable
squamous cell carcinoma of the skin. J. Clin. Oncol. 2011; 29: 3419–26.
24. Foote MC, McGrath M, Guminski A et al. Phase II study of single-
agent panitumumab in patients with incurable cutaneous squamous cell
carcinoma. Ann. Oncol. 2014; 25: 2047–52.
25. William WN Jr, Feng L, Ferrarotto R et al. Gefitinib for patients with
incurable cutaneous squamous cell carcinoma: a single-arm phase II
clinical trial. J. Am. Acad. Dermatol. 2017; 77: 1110–13.e2.
14452197, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ans.16584 by Unsw Library, Wiley Online Library on [19/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Yang et al.
26. Gold KA, Kies MS, William WN Jr, Johnson FM, Lee JJ, Glisson BS.
Erlotinib in the treatment of recurrent or metastatic cutaneous squamous
cell carcinoma: a single-arm phase 2 clinical trial. Cancer 2018; 124:
2169–73.
27. Guminski A, Stein B. Immunotherapy and other systemic therapies for
cutaneous SCC. Oral Oncol. 2019; 99: 104459.
28. Migden MR, Khushalani NI, Chang ALS et al. Cemiplimab in
locally advanced cutaneous squamous cell carcinoma: results from
an open-label, phase 2, single-arm trial. Lancet Oncol. 2020; 21:
294–305.
Supporting information
Additional Supporting Information may be found in the online ver-
sion of this article at the publisher’s web-site:
Table S1. Radiotherapy details.Table S2. Treatment
complications.Table S3. Univariate analysis of predictors of
disease-free survival, overall survival, regional recurrence and dis-
tant recurrence.
© 2021 Royal Australasian College of Surgeons