Multimodal Therapy in

the M anagement o f
A d v a n c e d Pe n i l e C a n c e r
Praful Ravi, MBBChira, Lance C. Pagliaro, MDb,*

KEYWORDS
 Penile cancer  Adjuvant chemotherapy  Neoadjuvant chemotherapy  Survival  Radiotherapy

KEY POINTS
 A multimodal approach to therapy is increasingly used in treating men with advanced penile cancer.
 Adjuvant chemotherapy is associated with improved outcomes in chemotherapy-naı̈ve men with
node-positive penile cancer.
 Neoadjuvant systemic chemotherapy may downstage regional lymph node metastases sufficiently
to permit surgery while imparting a potential improvement in long-term disease-free survival.
 International collaboration in clinical trials is required to optimize treatment and improve survival in
men with advanced penile cancer.

INTRODUCTION N1-3 and/or M1 disease); 28% to 64% of men

Squamous cell carcinoma (SCC) of the penis is a
rare disease, with an estimated 2020 cases and
340 deaths in the United States this year.1 Prog-
nosis is good if disease is diagnosed at a localized
stage, but up to 40% of patients present with
locally advanced or metastatic disease and out-
comes for these patients have historically been
poor.2,3 The disease typically spreads in a locore-
gional manner, first to the draining inguinal
lymph nodes, then to pelvic nodes, and then to
viscera. The organized nature of spread makes
the disease a candidate for a multimodal therapeu-
tic approach, which has been successfully used to
treat other SCCs, such as head and neck,4 anus,5
or vulva.6 The rarity of penile cancer in the United
States and Western Europe, however, has
hampered clinical study into the treatment of
locally advanced or metastatic disease and there
are currently no randomized data in this setting.
The TNM staging system for penile cancer is
shown in Table 1. Advanced disease implies
spread beyond the local tissues (ie, T3-4 and/or
with penile cancer present with clinically palpable
inguinal lymph nodes. In such cases, metastatic
disease underlies lymphadenopathy in 47% to
85% of such individuals, with the remainder due
to inflammatory nodal reaction, and the risk of
pelvic nodal metastases is 22% to 56% if the
inguinal nodes are involved.7–9 The most important
prognostic factor in penile cancer is the presence
of inguinal lymph node metastases, with the
number of positive lymph nodes, bilateral inguinal
nodal disease, pelvic nodal involvement, and
extranodal metastatic extension imparting a worse
prognosis.10 When inguinal lymphadenopathy is
not clinically apparent, micrometastatic disease
is present in approximately 25% of cases, with
predictive risk factors including tumor stage,
grade, and lymphovascular invasion.11
ADJUVANT CHEMOTHERAPY IN
NODE-POSITIVE DISEASE
A multimodal approach can be used to treat men
who are found node-positive after undergoing
urologic.theclinics.com

The authors declare no conflicts of interest and no funding source.

a
Department of Internal Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA;
b
Department of Oncology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
* Corresponding author.
E-mail address: pagliaro.lance@mayo.edu

Urol Clin N Am 43 (2016) 469–479

http://dx.doi.org/10.1016/j.ucl.2016.06.008
0094-0143/16/Ó 2016 Elsevier Inc. All rights reserved.
470 Ravi & Pagliaro

Table 1
radical inguinal lymphadenectomy. Although there
TNM staging system for penile cancer is evidence to support the use of adjuvant chemo-
therapy in men with pN2 or pN3 disease, this is
T – primary tumor based on small numbers of patients and single-
Tx: Cannot be assessed center or multicenter retrospective data.
T0: No evidence of primary tumor The largest patient series reporting outcomes
Tis: Carcinoma in situ of adjuvant chemotherapy for penile cancer was
Ta: Noninvasive carcinoma recently published and combined data from 4 ter-
T1a: Tumor invades subepithelial tissue tiary centers in the United States, Netherlands,
without LVI and is not poorly
Italy, and China.12 The investigators identified
differentiated/undifferentiated
T1b: Tumor invades subepithelial tissue with
84 men who underwent lymph node dissection
LVI or is poorly-differentiated/ for SCC of the penis between 1978 and 2013
undifferentiated and who were found to have positive pelvic lymph
T2: Tumor invades corpus spongiosum and/or nodes (ie, pN3). In this cohort, 36 men received
cavernosum adjuvant chemotherapy, with a majority (78%)
T3: Tumor invades urethra treated with platinum-based regimens (most
T4: Tumor invades other adjacent structures commonly docetaxel, cisplatin, and 5-fluorouracil
N – regional lymph nodes [TPF]), whereas 48 were not. At a median follow-
Nx: Cannot be assessed up of just over 12 months, median overall survival
N0: No palpable or visibly enlarged inguinal
was significantly greater in those who had
lymph node
N1: Palpable mobile unilateral inguinal
received chemotherapy compared with those
lymph node who had not (21.7 months vs 10.1 months,
N2: Palpable mobile multiple unilateral or P 5 .048) (Fig. 1). Furthermore, receipt of adju-
bilateral inguinal lymph nodes vant chemotherapy (hazard ratio [HR] 5 0.40
N3: Fixed inguinal nodal mass or pelvic [0.19–0.87], P 5 .021) was the sole independent
lymphadenopathy, unilateral or bilateral predictor of overall survival in a multivariable
M – distant metastasis analysis adjusting for age, pathologic stage, bilat-
M0: No distant metastasis erality of nodal disease, and timing of pelvic
M1: Distant metastasis surgery.
Pathologic classification
There are several important limitations of this
pNX: Cannot be assessed
study, however, the most important being that
pN0: No regional lymph node metastasis
pN1: Metastasis in a single inguinal lymph men who had received salvage chemotherapy af-
node ter disease recurrence were excluded, which
pN2: Metastasis in multiple or bilateral may have led to a systematic bias. The group
inguinal lymph nodes who had not received adjuvant chemotherapy
pN3: Extranodal extension of lymph node likely included men who had been unable to
metastasis or pelvic lymph node(s) receive it owing to rapid postoperative disease
metastasis recurrence or poor postoperative recovery. In
Anatomic staging contrast, the group who did receive adjuvant
Stage 0 Tis N0 M0 chemotherapy was probably enriched by men
Ta N0 M0 who had recovered quickly after surgery
Stage I T1a N0 M0 (and were thus able to tolerate chemotherapy)
and then never recurred, thereby never requiring
Stage II T1b N0 M0
T2 N0 M0 salvage chemotherapy. In addition to this and
T3 N0 M0 potentially other selection biases, the study was
Stage IIIA T1-3 N1 M0 inadequately powered for a multivariable analysis.
Other data on the role of adjuvant chemotherapy
Stage IIIB T1-3 N2 M0
for pathologic node-positive penile cancer come
Stage IV T4 Any N M0 from smaller, single-center studies. The earliest
Any T N3 M0
data on adjuvant treatment came from a pilot
Any T Any N M1
study in Milan, Italy, that was published in the
Abbreviation: LVI, lymphovascular invasion. late 1980s.13 Twelve men who had undergone
Adapted from Sobin LH, Gospodariwicz M, Wittekind C, unilateral or bilateral lymphadenectomy for penile
editors. TNM classification of malignant tumors. UICC
cancer, including 5 who had pelvic nodal disease,
International Union Against Cancer. 7th edition. Oxford:
Wiley-Blackwell; 2009. p. 336. received weekly vincristine, bleomycin, and meth-
otrexate (VBM) for 12 weeks, with 11 of the 12 pa-
tients (92%) alive and disease-free at a median
 Multimodal Therapy for Advanced Penile Cancer
follow-up of 42 months. There were 2 cases of
bleomycin-induced lung injury, however.
Poorer survival outcomes were reported in a
small German case series evaluating adjuvant
bleomycin, methotrexate, and cisplatin (BMP).
Three of 8 men (38%) with pN1-3 disease were
alive and free of disease at a mean of 4.5 years after
adjuvant treatment, and 1 individual died as a result
of lung toxicity secondary to bleomycin.14 Doublet
(rather than triplet) chemotherapy has also been
investigated in the adjuvant setting in an effort to
reduce toxicity and this approach was shown to
achieve good outcomes in a retrospective study
from Mumbai, India. A combination of paclitaxel
with either carboplatin or cisplatin was used in 19
men with high-risk locally advanced disease
(defined as perinodal extension, bilateral nodal
involvement, and pelvic node disease and those
with incomplete surgical resection) and produced
a 2-year overall survival of 68%.15 At a median
follow-up of 15 months, 6 men (32%) had suffered
a locoregional relapse, and 3 died (2 due to disease
and 1 treatment-related death secondary to diar-
rhea and neutropenic fever).
The latest data on adjuvant therapy from the
Milan group recorded disappointingly poor out-
comes in 19 men with pN2 or pN3 disease who
received adjuvant cisplatin and 5-FU in combina-
tion with a taxane (paclitaxel or docetaxel), termed
471
Fig. 1. Overall survival stratified by
receipt of adjuvant (adj.) chemo-
therapy in chemotherapy-naı̈ve men
with pelvic node-positive penile
cancer. (From Sharma P, Djajadining-
rat R, Zargar-Shoshtari K, et al.
Adjuvant chemotherapy is associated
with improved overall survival in
pelvic node-positive penile cancer
after lymph node dissection:
a multi-institutional study. Urol
Oncol 2015;33(11):496.e20; with
permission.)
TPF, with a 2-year disease-free survival of 37%.16
Additionally, there was substantial hematologic
toxicity, with 6 cases of grade 3 or 4 anemia, neu-
tropenia, or thrombocytopenia. These investiga-
tors recently evaluated factors associated with
better outcomes in men who received adjuvant
TPF and found that that p53 immunohistochemical
positivity in the nodal metastasis seemed to pre-
dict for poorer disease-free survival (HR 5 3.76
[0.78–17.96], P 5 .096) and overall survival
(HR 5 4.29 [0.89–20.57], P 5 .067) in multivariate
analyses, although results did not reach statistical
significance.17 These preliminary results are hy-
pothesis generating and merit further study in
ongoing efforts to determine which men with
advanced penile cancer might benefit most from
adjuvant therapy.
Summary
Table 2 summarizes the current available evi-
dence on the role of adjuvant chemotherapy in
node-positive penile cancer. There are no random-
ized data, and reported follow-up is short, which
raises questions on whether a survival benefit
from adjuvant chemotherapy can be durable, while
attempts to define predictive and prognostic fac-
tors are at a very early stage. Although a majority
of patients received a platinum-based regimen,
472 Ravi & Pagliaro

Table 2
Summary of studies on adjuvant chemotherapy in node-positive penile cancer

Median
(Mean)
Follow-up,
Citation Patient Cohort N Regimen mo Survival Outcomes Toxicity
Pizzocaro & Involved inguinal 12 VBM 42  11 Alive and dis- Bleomycin-induced
Piva,13 and/or pelvic ease-free lung damage
1988 nodes  1 Died of disease (n 5 2)
Hakenberg pTx pN1-3 M0 8 BMP (54)  3 Alive and dis-  Treatment-
et al,14 ease-free related death
2006  4 Died of disease (n 5 1)
 1 Treatment-  Any grade 3 or 4
related death (n 5 24/45)
Noronha High-risk nodal 19 TP 15  2-Year OS 5 68%  Treatment-
et al,15 disease (PNE,  6 Locoregional related death
2012 bilateral nodal relapses (n 5 1)
disease, pelvic  2 Died of disease  Any grade 3 or 4
nodal disease,  1 Treatment- (n 5 6)
R1 resection) related death
Nicolai pN2 M0 19  TPF (n 5 16) N/A  10 Alive and dis- Any grade 3 or 4
et al,16  Paclitaxel-PF ease-free (n 5 10)
2015 (n 5 3)  8 Died of disease
 1 Died of other
cause
 2-Year DFS of
37%
Sharma pN3 M0 36  TPF (n 5 18) 12  mOS 5 21.7 mo N/A
et al,12  PF (n 5 8) (vs 10.1 mo in a
2015  VBM (n 5 8) cohort of 48 men
 TIP (n 5 1) who did not
 BMP (n 5 1) receive adjuvant
chemotherapy),
P 5 .048
 Adjuvant
chemotherapy
HR for OS 5 0.40
(0.19–0.87),
P 5 .021

Abbreviations: DFS, disease-free survival; mOS, median overall survival; N/A, not available; PF, cisplatin, 5-FU; PNE, perinodal
extension; OS, overall survival; TP, paclitaxel, cis/carboplatin.

the optimal combination (doublet or triplet) is also
yet to be defined. Nevertheless, taken together,
adjuvant platinum-based therapy does have a
role in the management of chemotherapy-naı̈ve
patients with pelvic node-positive penile cancer,
given the premise that it offers the possibility of
long-term survival in this cohort of men who might
otherwise be expected to relapse without adjuvant
treatment.
MULTIMODAL APPROACH TO BULKY OR
UNRESECTABLE NODAL DISEASE
Surgery alone is rarely a curative option in
men with advanced inguinal or pelvic nodal
disease. Bilateral, numerous, and bulky inguinal
involvement; extranodal extension; and the pres-
ence of pelvic nodal metastases are known
prognostic factors in penile cancer, and a multi-
modal approach is desirable in treating patients
with these features.3,18,19
Neoadjuvant chemotherapy offers the ability to
downstage disease and thereby enable surgical
resection among responders, even among men
with advanced penile cancer. Data from the
Southwest Oncology Group phase II trial of BMP
included examples of bulky inguinal lymph node
disease that had a partial response (4 patients)
or complete response (2 patients).20 Details of
postchemotherapy surgery were not reported in
 Multimodal Therapy for Advanced Penile Cancer
that study, and although a response was seen in
nearly 1 in 3 men (including lymph node and
distant metastases), toxicity with BMP was signif-
icant, with 5 treatment-related deaths (from infec-
tion or pulmonary complications) among 45
registered patients.
Building on these results, Leijte and col-
leagues21 from the Netherlands reported the out-
comes in 20 patients who received neoadjuvant
chemotherapy for M0 penile cancer between
1972 and 2005. Although there was heterogeneity
in the regimens used (VBM; BMP; 5-FU and
cisplatin; cisplatin and irinotecan; and single-
agent bleomycin), an overall response (either com-
plete or partial response) was seen in 12 of 19
evaluable patients (63%). Importantly, 8 of the 9
responders who went on to undergo lymphade-
nectomy had durable long-term survival with no
evidence of disease recurrence at a median
follow-up of 20 months, with 2 having a pathologic
complete response (pCR) on postoperative histol-
ogy. Response to neoadjuvant therapy was also
prognostic, with a 56% 5-year overall survival in
men who responded, whereas all nonresponders
had died within 9 months of treatment.
The similarities between SCC of the penis and
head and neck have prompted study of alternative
neoadjuvant regimens. The Milan group reported
retrospective data on their experience with neoad-
juvant TPF, the overall results of which seem
slightly poorer compared with the Dutch data. A
median of 4 cycles of TPF was administered to
28 men with clinical N3 disease, producing an
overall response rate of 43%.16 Of the 22 men
who subsequently underwent surgery, 7 (32%)
were alive and disease-free at a median follow-
up of more than 12 months, including 2 of the 4
who achieved a pCR. In the entire cohort, how-
ever, 12 men relapsed and 9 died of disease,
with an additional 3 deaths due to other causes,
including 1 treatment-related death from cardiac
toxicity. Response to treatment was also not asso-
ciated with survival, although the study was under-
powered to assess this.
These retrospective data served to confirm that
neoadjuvant chemotherapy is feasible and poten-
tially effective as part of a multimodal approach
against advanced penile cancer. Four prospective
studies have added to the evidence base but the
small numbers of patients they have accrued
make it difficult to generate robust conclusions.
The European Organisation for Research and
Treatment of Cancer (EORTC) conducted a multi-
center phase II study of neoadjuvant irinotecan in
combination with cisplatin in 7 men with T3 or
N1-2 disease.22 A median of 4 cycles of treatment
was administered, and 2 men (29%) achieved a
473
clinical response, with a pCR seen in 3 men who
underwent postchemotherapy resection.
Investigators at the University of Texas MD
Anderson Cancer Center conducted the largest
prospective study of neoadjuvant chemotherapy
for locally advanced disease in the form of a phase
II trial enrolling 30 men with clinical stage Tx N2-3
M0 disease, a majority of whom (70%) had clinical
N3 disease at baseline.23 Patients received 4 cy-
cles of paclitaxel, ifosfamide, and cisplatin (TIP)
prior to planned bilateral inguinal and unilateral or
bilateral pelvic lymphadenectomy. The treatment
was well tolerated, with a majority of men
completing all 4 planned cycles and grade 3 infec-
tion the most commonly observed adverse event
(on 5 occasions). All but 4 individuals went on to
undergo lymphadenectomy, including 22 of the
23 men who completed all 4 cycles of chemo-
therapy. The objective response rate, measured
by Response Evaluation Criteria in Solid Tumors
(RECIST), was 50% (with 3 complete responses
and 12 partial responses) and 3 men had a pCR
(13.6%). Survival outcomes were comparable to
those seen in retrospective studies,16,21 with 9
men (30%) remaining alive and disease-free at a
median follow-up of 34 months, with a reported
median overall survival within the entire cohort of
17 months. Response to neoadjuvant TIP also pre-
dicted for longer time to disease progression and
overall survival (Fig. 2). Postoperative complica-
tions were comparable to those seen in contem-
porary lymphadenectomy series,24 suggesting
that neoadjuvant chemotherapy did not increase
surgical morbidity.
The same investigators subsequently published
a follow-up report by retrospectively reviewing re-
sults from an additional 31 men with Tx N1-3 M0
disease who underwent neoadjuvant chemo-
therapy, predominantly with TIP, to produce an
overall cohort of 61 patients.25 This report included
21 men who had undergone a prior inguinal proce-
dure and were being treated for disease recur-
rence or persistence. There was an impressive
overall response rate of 65% (39 of 61 men), and
the vast majority (85%) went on to undergo sur-
gery, with 10 men (19%) achieving a pCR; 50%
of the chemotherapy responders were alive and
disease-free at a median follow-up of more than
5 years, as were 7 of the 10 whose surgery had
revealed a pCR, suggesting that this multimodal
approach to advanced penile cancer had contrib-
uted to the observed long-term survival.
Prospective studies of other platinum-based
regimens in the treatment of metastatic penile can-
cer have not been as successful as the MD Ander-
son experience with TIP. A well-designed phase II
trial in the United Kingdom involving 21 men with
474 Ravi & Pagliaro

Fig. 2. Kaplan-Meier curves showing (A) time to disease progression, (B) overall survival in men receiving neoad-
juvant TIP, and (C) time to progression, and (D) overall survival stratified by response to neoadjuvant chemo-
therapy, respectively. The 95% CIs are shown (A, B) with dashed lines above and below. (From Pagliaro LC,
Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic
penile cancer: a phase II study. J Clin Oncol 2010;28(24):3854; with permission.)

Tx N1-3 M0 penile cancer (a majority of whom had
N3 disease) aimed to assess response clinically
and via RECIST after a planned 3 cycles of TPF
and determine how many patients subsequently
became operable.26 The overall response rate
was 37% in men with evaluable locally advanced
disease, and 5 of 20 patients who were deemed
inoperable at trial entry were sufficiently down-
staged to proceed with surgery. Toxicity with
TPF was substantially greater than that with TIP,
however, with more than 2 in 3 patients suffering
any grade 3 or 4 adverse events.
The most recent prospective study examining
the role of neoadjuvant chemotherapy comes
from the Netherlands Cancer Institute and was
published in 2015.27 They used neoadjuvant TPF
as part of a nonrandomized institutional study
(with a higher dose of cisplatin than that used in
the previously described UK TPF phase II trial26)
in 26 men with T4 and/or N3 disease and aimed
at downstaging men sufficiently to permit surgery.
Almost half of the cohort completed all of the
planned 4 cycles, and complete and partial re-
sponses (per RECIST) were seen in 2 and 9 pa-
tients, respectively, giving an overall response
rate of 44% in the 25 evaluable patients. An addi-
tional 4 men achieved stable disease, and of the
15 individuals in whom stable disease or better
was attained, 14 underwent surgery, with 1 patient
having a pCR. Taking into consideration the het-
erogeneity of the cohort (almost half were treated
for recurrent disease, thereby potentially selecting
for more aggressive disease biology), survival out-
comes were still disappointing. Only 4 men (15%)
were alive and disease-free at a median follow-up
of 30 months and median overall survival was
10 months, compared with the 17 months seen
with TIP. Furthermore, 6 men discontinued therapy
owing to toxicity, and all enrolled men experienced
at least grade 2 or higher toxicity.
Summary
Table 3 summarizes currently published evidence
on the use of neoadjuvant chemotherapy for
locally advanced penile cancer. A response rate
of 29% to 65% has been seen with the use of neo-
adjuvant chemotherapy and it is an important part
of the multimodal approach to treat advanced
penile cancer. The disease seems most sensitive
 Table 3
Summary of studies on neoadjuvant chemotherapy for unresectable nodal disease

Pathologic
Complete
Response at
Median Response Underwent Surgery (% of
Citation Patient Cohort N Regimen(s) Follow-up, mo Rate, % Surgery (%) Those Operated) Survival Outcomes
Leijte et al, 21
2007 Tx N0-3 M0 20 BMP (n 5 10) 23 63 9 (45) 2 (22)  5-Y OS 5 32%
VBM (n 5 5)  8 of 9 undergoing
Bleomycin (n 5 3) surgery alive and
PF (n 5 1) disease-free at
Cisplatin-irinotecan median follow-up
(n 5 1) of 20 mo
Theodore et al,22 T3 N1-2 M0 7 Cisplatin-irinotecan N/A 29 3 (43) 3 (100) N/A
2008
Pagliaro et al,23 2010 Tx N2-3 M0 30 TIP 34 50 22 (73) 3 (14)  9 Alive and disease-

Multimodal Therapy for Advanced Penile Cancer

free
 mOS 5 17 mo
Dickstein et al,25 Tx N1-3 M0 (including 61 TIP (n 5 53) N/A 65 52 (85) 10 (19)  20 Alive and
2016a prior inguinal TP, PF, BMP (n 5 7) disease-free at 5 y
procedure)  32 Died of disease
at 5 y
Nicolai et al,16 2015 Tx N3 M0 (including 5 28 TPF (n 5 23) N/A 43 22 (79) 4 (18)  8 Alive and disease-
with relapsed Paclitaxel-PF (n 5 5) free
disease)  9 Died of disease
 2-Year DFS 5 7%
Djajadiningrat et al,27 T4 and/or N3 26 TPF 30 44 14 (54) N/A  4 Alive and disease-
2015 (including 12 with free
relapsed disease)  13 Died of disease
 mOS 5 10 mo
 1-Year OS 5 46%
 2-Year OS 5 27%
Abbreviations: DFS, disease-free survival; mOS, median overall survival; N/A, not available; PF, cisplatin, 5-FU; OS, overall survival; TIP, paclitaxel ifosfamide, cisplatin; TP, paclitaxel, cis/
carboplatin.
a
This study included patients from Pagliaro and colleagues, 2010.23
Data from Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Oncol
2010;28(24):3851–7.

475
476 Ravi & Pagliaro
to platinum-based therapy, with TIP offering the
highest response rates. Translating response into
a durable survival benefit, however, has proved
difficult and optimizing this multimodal approach
to do so requires further study. Nevertheless, cur-
rent European Association of Urology28 and Na-
tional Comprehensive Cancer Network29
guidelines recommend the use, wherever feasible,
of a triplet regimen, including cisplatin and a tax-
ane, followed by consolidation surgery in men
with bulky or initially unresectable nodal disease
who respond to neoadjuvant chemotherapy.
IS THERE A ROLE FOR
CHEMORADIOTHERAPY?
The question of whether chemoradiotherapy may
be a feasible option for men with locally advanced
and regionally metastatic penile cancer has been
raised owing to the superiority of this approach
compared with single-modality therapy alone in
the treatment of locally advanced SCCs of the
vulva and anus, 2 rare perineal tumors that share
anatomic and biologic characteristics with penile
cancer.5,6,30 Concurrent chemoradiation has also
gained traction because neoadjuvant radiotherapy
has been shown to reduce inguinal recurrence
rates in men with bulky nodal disease,31 offering
the possibility of synergistic activity with neoadju-
vant chemotherapy.
The data on chemoradiotherapy for advanced
penile cancer are limited to case reports and
case series. The sole multicenter study examining
chemoradiation collated data between 2000 and
2012 from 5 tertiary centers in the United States,
Canada, and Italy.32 In this 26-patient cohort,
including 16 men with clinical stage IV disease
and 5 with M1 disease, a majority received
cisplatin-based chemotherapy together with a
median dose of 4900 cGy to involved disease
areas. Accepting that most patients had stage
IV disease at outset and that men with relapsed
disease were also included, however, clinical
outcomes were disappointing: 1-year overall
survival was 37% in men with M0 disease, a
figure that is less than that achieved with neoad-
juvant chemotherapy alone followed by surgical
consolidation.23
The extreme paucity of data on chemoradiation
for advanced penile cancer, therefore, means that
this approach is currently investigational, requiring
further evaluation within clinical trials, a sentiment
that is reflected in consensus guidelines.28 It is,
however, a reasonable treatment option for pa-
tients who refuse surgery or are deemed inoper-
able despite receiving neoadjuvant systemic
chemotherapy.
THE NEED FOR MULTICENTER
COLLABORATION
The rarity of penile cancer means that international
and multicenter collaboration is an absolute ne-
cessity to enable sufficient accrual of patients
into clinical trials such that clinically meaningful re-
sults may be produced. The 4 phase II trials of
neoadjuvant chemotherapy22,23,26,27 accrued a
combined total of 84 patients across 15 years.
The UK study26 was able to recruit 21 men in just
15 months, which was in part due to the enrollment
of patients treated at 9 specialist centers, high-
lighting the role that collaboration between centers
of expertise can play in improving patient recruit-
ment into trials for a rare cancer.
To this end, the UK National Institute for Health
Research Cancer Research Network, Cancer
Research UK, the US National Cancer Institute,
and the EORTC came together in 2011 to form
the International Rare Cancers Initiative (IRCI),
which aims to facilitate the development of inter-
national clinical trials for patients with rare
cancers, including penile cancer.33 The Interna-
tional Penile Advanced Cancer Trial (InPACT;
NCT02305654) (Fig. 3)34 is the first such IRCI trial
for penile cancer and plans to recruit 400 men
with locally advanced (ie, nodally metastatic)
penile cancer. Men first will be randomized either
to standard surgery (inguinal lymphadenectomy),
neoadjuvant chemotherapy (with TIP) followed by
consolidation surgery, or neoadjuvant chemora-
diotherapy (45 Gy in 25 fractions over 5 weeks
with weekly cisplatin as a radiosensitizer) followed
by surgery. Those who are deemed at high risk of
recurrence after inguinal lymphadenectomy will
subsequently be randomized to receive either pro-
phylactic pelvic lymphadenectomy or no further
surgery. The primary outcome will be overall sur-
vival, with secondary outcomes measures,
including disease-specific survival, pathologic
complete remission rates, quality of life, and surgi-
cal complication rates. This trial, which is yet to
open, represents a landmark event in the penile
cancer field and will provide the first randomized
data in the advanced disease setting. It is also
hoped that it will open the door to further multi-
institutional collaboration, which is crucial in
providing physicians with a robust evidence base
on which to base treatment decisions for men
with advanced penile cancer.
SUMMARY
Although penile cancer remains a rare disease,
significant progress has been made in developing
an evidence base to support the use of a
 Multimodal Therapy for Advanced Penile Cancer 477

Tx N1-3 M0 squamous Fig. 3. InPACT trial design. ILND,

cell carcinoma, n = 400 inguinal lymph node dissection;
IMRT, intensity-modulated radio-
randomized therapy; PLND, pelvic lymph node
dissection; RT, radiotherapy.

ILND Neoadjuvant Neoadjuvant chemoradiotherapy

TIP + ILND (IMRT 45Gy/25 Fr + weekly
cisplatin) + ILND

High-risk nodal histology

randomized

Adjuvant chemoradiotherapy
Prophylactic PLND (or surveillance if given preoperative RT)

multimodal approach to regionally metastatic dis-
ease (Fig. 4). Prospective data have shown that
neoadjuvant chemotherapy, with TIP seeming the
most active regimen followed by surgical consoli-
dation, has the potential to lead to a durable
long-term survival, at least in some men. Adjuvant
chemotherapy also improves outcomes for men
who have undergone lymphadenectomy for
resectable disease and who are chemotherapy
naı̈ve.
There remain several unanswered questions in
the treatment of advanced penile cancer. What
factors predict for response to (neo)adjuvant
chemotherapy and are prognostic for survival? Is
there a role for concurrent chemoradiotherapy?
Is it possible to stratify patients by their molecular
status or HPV positivity, and how can newer tar-
geted therapies be integrated into the current
multimodal treatment paradigm? The answers to
these questions will come from international

Assess primary and nodes for resectability

Resectable Unresectable

Risk factors
-LN ≥4 cm
Yes Neoadjuvant chemotherapy
-≥2 +ve nodes
-ENE (clinical)
-Pelvic nodes

No Progression or unresectable Response or resectable

ILND Palliative chemo- or radiotherapy ILND

High-risk
Low-risk -≥2 +ve nodes Consider PLND
-0–1 +ve nodes -ENE

Consider postoperative
Adjuvant chemotherapy Consider neoadjuvant radiotherapy if >pN0
or surveillance chemotherapy and PLND

Fig. 4. Summary of current approach to multimodal therapy in men with locoregionally advanced squamous cell
penile cancer. 1ve, positive; ENE, extranodal extension; ILND, inguinal lymph node dissection; LN, lymph node(s);
PLND, pelvic lymph node dissection.
478 Ravi & Pagliaro
collaboration across clinical trials, of which the au-
thors hope InPACT to be the first of many.
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