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MOU 300229

REVIEW

CURRENT
OPINION Neoadjuvant chemotherapy for lymph node-positive
penile cancer: current evidence and knowledge
Marco Bandini a, Filippo Pederzoli a, and Andrea Necchi b

Purpose of review
To review the latest in penile cancer treatment focusing on neoadjuvant chemotherapy in patients with
regional lymph node involvement.
Recent findings
Patients with regional lymph node involvement from penile cancer still suffer from a poor prognosis, and
the chances to achieve cure are primarily dependent on the extent of the disease. Despite multiple lines of
research are indicating the need for a multimodal management of the disease upfront, the search for newer
effective systemic therapies is ongoing. The available guidelines currently suggest the use of combination
chemotherapy regimens including taxanes and cisplatin as induction therapy before lymphadenectomy in
patients with locally advanced disease (i.e., fixed or bulky inguinal lymph nodes or pelvic lymph node
involvement). Research in the field will aim to provide more effective systemic therapies also in patients with
a more limited disease spread to further improve the outcomes. Data from the literature also indicate the
possibility to effectively administer postoperative chemotherapy in selected high-risk patients.
Summary
We aimed to provide the evidence from the literature and the new avenues that would help delineating
the optimal therapeutic pathway for these complex patients, commenting on the new opportunities that
may come from the ongoing research.
Keywords
lymphadenectomy, neoadjuvant chemotherapy, penile cancer, squamous cell carcinoma, systemic therapies

INTRODUCTION PATIENT SELECTION AND TREATMENT

Penile squamous cell carcinoma (PSCC) is a highly
aggressive disease characterized by a high risk of
early locoregional spread and morbidity with subse-
quent potential for distant dissemination [1–3].
PSCC is relatively rare in developed or Western
countries, but considerable variability in regional
incidences has been observed in different parts of
the world, partly depending on the epidemiology of
human papillomavirus (HPV) infection [4,5]. Con-
sequently, clinical research in the field, and in par-
ticular in locally advanced or metastatic disease
states, suffered from the typical limitations of the
rare disease. Data from the literature indicate that
the results achieved from prospective clinical trials
are very limited, and most of the knowledge that is
currently sustaining the available recommendations
and guidelines is based on retrospective studies
[6,7]. In this present article, we have performed a
critical review of the most recent literature with the
aim to update on the role of neoadjuvant chemo-
therapy in patients with regional lymph node
involvement from penile cancer.
GUIDELINES
Presence of bulky or fixed inguinal lymphadenopa-
thy uniformly signifies metastatic disease, and only
a small portion of these patients will benefit from
surgery alone. As of today, regional lymph node
dissection is the standard-of-care for locally
advanced PSCC, and the importance of high-qual-
ity, timely surgical resection has been recently cor-
roborated by international retrospective, individual
patient-level data analyses [8,9,10,11–13,14]. Pre-
surgical systemic therapy in these patients is an
a
Unit of Urology, Division of Experimental Oncology, Urological Research
Institute (URI), IRCCS Ospedale San Raffaele and bDepartment of
Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori,
Milan, Italy
Correspondence to Andrea Necchi, MD, Department of Medical Oncol-
ogy, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1,
20133 Milano, Italy. Tel: +39 02 2390 2402; fax: +39 02 2390 3150;
e-mail: andrea.necchi@istitutotumori.mi.it
Curr Opin Urol 2020, 30:000–000
DOI:10.1097/MOU.0000000000000719

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MOU 300229
Penis cancer
KEY POINTS
 Current retrospective evidence supports the use of
neoadjuvant chemotherapy only in patients with fixed
or bulky inguinal lymph nodes or pelvic lymph
node involvement.
 If considered, combination of taxanes and platin-based
chemotherapy is the referral regimen for
neoadjuvant chemotherapy.
 Although combination of 5-FU with cisplatin and
docetaxel (TPF) may improve the overall survival benefit
in a subset of patients, these findings should be
interpreted with caution because of the high toxicity of
the chemotherapy regimens, conflicting retrospective
data, and the lack of prospective evidence
attractive treatment paradigm because it allows
timely delivery of therapy to treat systemic disease,
results in volume-reduction of inguinal lymphade-
nopathy, and facilitates future surgical consolida-
tion. Several retrospective studies using various
chemotherapeutic agents reported objective
response rates (ORR) ranging 20–50% and complete
response (CR) rates of 10–20% in patients who
underwent consolidative inguinal  pelvic lymph
node dissection after induction therapy [15,16]. In
patients with multiple, fixed, or bulky inguinal
lymph nodes, multimodality therapy including
neoadjuvant chemotherapy followed by lymph
node resection is preferred or even recommended
according to the European Association of Urology
(EAU) and the National Comprehensive Cancer
Network guidelines [1,17]. On the other hand, neo-
adjuvant chemotherapy can be associated with con-
sistent risk of toxicity, especially when combined
agents are administered. Here, severe (grade 2–3)
toxicity might range between 20 and 25% according
to different series [18–20].
Among the few landmark clinical trials of
systemic therapy conducted in PSCC, we have
the phase II trial conducted by Pagliaro et al. [20].
The investigators evaluated the activity of the triple
combination of paclitaxel, ifosfamide, and cisplatin
(TIP) in patients with clinical stage N1–2 PSCC.
This study showed that of the patients who received
this regimen, 50% had an objective response and
73% were downstaged and subsequently underwent
surgery; response to chemotherapy was significantly
associated with both increased time to progression
(TTP) and overall survival (OS, P < 0.001 and
P ¼ 0.001, respectively). Nine patients (30.0%)
remained alive and free of recurrence after a median
follow-up of 34 months. The estimated median
TTP was 8.1 months, long-term progression-free
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survival rate was 36.7%, and the median OS was
17.1 months.
The alternative chemotherapy regimen used in
the modern era, which has emerged from a prospec-
tive study, and from multiple large retrospective
studies, was represented by the combination of
5-fluorouracil (5-FU) with cisplatin and docetaxel
(TPF).
In the clinical trial conducted in United King-
dom, the partial response (PR) rate was 32% and,
most noteworthy, grade 3 or 4 neutropenia occurred
in 20% of the patients [21].
Other studies reporting results with the use of
TPF chemotherapy suggested that the ORR could
increase and be comparable with that achieved with
TIP chemotherapy, and in more advanced patients
(clinical N3, or those with multiple lymph node
recurrences after surgery) [18,22]. Therefore, pend-
ing additional results from prospective clinical
trials, TIP or TPF chemotherapy could be equally
offered to patients with locally advanced PSCC who
are fit enough to tolerate combination regimens
[limited to Eastern Cooperative Oncology Group
performance status (ECOG-PS) 0] and have good
renal function tests.
ONCOLOGICAL OUTCOMES AFTER
NEOADJUVANT CHEMOTHERAPY
The overall outcomes achievable with neoadjuvant
chemotherapy studies have been reported from an
analysis of a large retrospective multicenter dataset
that included several different regimens [15]. The
pathologic CR rate approximated 13%, the clinical
ORR was about 50%, although the 2-year OS esti-
mate remained suboptimal (35.8%). It should be
noted however that the majority of patients with
PSCC are elderly patients presenting with signifi-
cant comorbidities and frailty that usually contra-
indicate the use of aggressive chemotherapy. The
actual rate of patients who cannot access to stan-
dard chemotherapy options because of comorbidity
is not well defined in the literature, but presumably
very high and likely depending on the treatment
setting (referral center vs. community oncology
practice level).
In the attempt to improve the outcomes of these
patients by providing a more tolerable chemother-
apy, United Kingdom’s authors have reported the
results of a phase II trial of neoadjuvant/first-line
vinflunine in patients with locally-advanced or met-
astatic PSCC (VinCaP study): in 25 patients, the ORR
was 27% and the clinical benefit rate 45.5% [23].
Outdated data from small retrospective studies,
variously combining old chemotherapy options,
are no more recommended in these patients.
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Several new data have been recently published
from an ongoing international collaboration among
expert centers in PSCC. This initiative gathered data
from patients treated in United States, Europe,
United Kingdom, Brazil, and China, who underwent
any extent of regional lymph node dissection for
PSCC, with or without the use of perioperative
therapies.
In one of the latest studies, 689 lymphadenec-
tomy cases were analyzed: 86 (12.5%) received neo-
adjuvant chemotherapy (various regimens); 171
(24.8%) received adjuvant chemotherapy, and 74
&
(10.7%) received adjuvant radiotherapy [24 ]. Of
note, both neoadjuvant chemotherapy and adju-
vant chemotherapy were ineffective in clinical
stage N1–2 patients. Conversely, adjuvant chemo-
therapy only resulted in better, but not statistically
significant, OS in cN3 patients with pelvic nodal
disease. Furthermore, neoadjuvant chemotherapy
use seemed to negatively impact the OS in patients
with early-stage disease (N1–2). These findings,
although they should be considered with caution
because of the typical biases of retrospective studies,
may implicate that moderately-effective preopera-
tive chemotherapy may result in detrimental out-
comes if toxicity concerns will raise, causing
significant delays of potentially curative surgery
or determining a more difficult surgical resection
in frail patients. Unfortunately, medical and surgi-
cal safety issues cannot be reliably accounted for
when conducting retrospective research and this is
certainly another huge gap in the literature. As a
matter of fact, the ability to administer treatment in
more finely selected high-risk patients is another
argument in favor of adjuvant chemotherapy.
In the same paper, a nomogram was developed
predicting 12-month and 24-month OS based on
prespecified baseline patient characteristics and
treatments, including clinical stage and periopera-
&
tive chemotherapy [24 ]. Pending validation with
larger and external datasets, this tool could be used
for improving patient counseling and decision
making in complex cases. In fact, based on these
results, a few recommendations were provided,
indicating the use of perioperative chemotherapy
in clinical or pathologic N3 patients, and the
use of adjuvant radiotherapy in patients with path-
ologic N3 stage with the evidence of extranodal
extension.
ALTERNATIVE TREATMENT MODALITIES
IN ADVANCED CASES
Conflicting data have been reported regarding the
indications for adjuvant radiotherapy in patients
&
with extranodal extension [25 ,26,27]. In another
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Neoadjuvant chemotherapy for penile cancer Bandini et al.
recent retrospective study conducted in 93 patients
with PSCC, postoperative radiotherapy was found to
decrease the likelihood of disease recurrence in the
groin or pelvis only if extranodal extension was
&
absent [25 ]. Therefore, additional, preferably pro-
spective, studies are required to clarify the indica-
tions for patient selection to receive either
preoperative or postoperative systemic therapy,
and to receive adjuvant consolidation radiotherapy.
It should be noted that no benefit was observed from
the use of adjuvant radiotherapy in a systematic
review conducted by the EAU penile cancer guide-
lines panel [27].
In addition, the lack of data regarding the effi-
cacy of chemoradiation, and type of chemotherapy
to use in combination with radiotherapy, and the
efficacy of neoadjuvant chemoradiation strategies
currently represent huge gaps in the therapeutic
armamentarium.
Therefore, further lines of research will have to
delineate the profile of the optimal candidates for
upfront multimodal therapy versus surgery followed
by adjuvant therapies.
Disappointingly, it is still unclear whether the
advances in the knowledge of the underlying biol-
ogy of PSCC will help us improving the ability to
predict the outcome of patients. Efforts have been
made to better delineate the molecular features
associated with advanced and treatment-resistant
&&
disease [28 ]. In a recent effort to compare the
molecular alteration profiles of PSCC versus cutane-
ous SCC, potential targeted therapy opportunities in
PSCC included alterations in MTOR pathway (NF1
genomic alterations in 7% and PTEN GA in 4%),
DNA damage response pathway (BRCA2 and ATM
genomic alterations, each in 7%) and tyrosine kin-
ases (EGFR genomic alterations in 6%; FGFR3 and
ERBB2 genomic alterations each in 4%). Tumor
mutational burden was significantly higher in the
predominantly ultraviolet light-exposed cutaneous
SCC than PSCC, making the former potentially
more responsive to immune-checkpoint inhibitors
than PSCC. Microsatellite instability-high status
was extremely rare for PSCC, and CD274 (PD-L1)
amplification.
Developing novel therapies in these rare tumors
is even more difficult, and this is unlikely to be a
priority of current research in the field, pending the
optimization of the use of standard therapy options
that has been discussed above.
The most recent effort in the use of targeted
therapy for PSCC was conducted in a phase II trial
of the pan-HER tyrosine-kinase inhibitor dacomiti-
nib in chemonaive patient with PSCC, including
patients with regional lymph node involvement
only, prior to radical surgery [29].
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Penis cancer
The activity of single-agent dacomitinib was
modest in 28 unselected patients (the ORR was
32.1%), although the drug was well tolerated, poten-
tially better than combination chemotherapy.
Pending additional data from several phase I
trials that are evaluating immunotherapy combina-
tions in various cohorts of solid tumors, including
penile cancer, such as the United States National
Cancer Institute (NCI) ICONIC trial which is testing
the combination of ipilimumab, nivolumab,
and cabozantinib (NCT03866382). Yet, it remains
difficult nowadays to envision a role for novel ther-
apy combinations in early disease states, within
multimodal strategies.
Importantly, most of the unanswered questions
in the management of regionally-advanced PSCC
will be addressed in an ongoing multiinstitutional
phase III study that is evaluating the optimal treat-
ment modality in clinically lymph node-positive
PSCC. The InPACT study (NCT02305654) is based
on a Bayesian design implicating multiple randomi-
zation nodes, to ultimately answer important ques-
tions on the efficacy of surgical (extent or resection
to the pelvic lymph nodes) and perioperative thera-
pies (neoadjuvant and adjuvant chemotherapy and
radiotherapy) in these patients and inclusion of
patients in this study is certainly an added value
for the community of investigators dealing with
&&
these rare difficult tumors [30 ].
CONCLUSION
In conclusion, advances in the cure of patients with
lymph node-involved PSCC are proceeding at a slow
pace. This situation is mainly dependent on the
knowledge gaps related to the identification of per-
sonalized multimodal therapeutic pathways
according to the patient characteristics and disease
features. Current evidence suggests that neoadju-
vant chemotherapy might be of some benefit only
in N3 patients. However, these findings should be
considered with caution because of the typical
biases of retrospective studies. Prospective studies
aimed at improving these gaps are certainly
required and, pending widespread application of
advanced knowledge in the field, centralization
to referral centers where research is being con-
ducted on large datasets may have an impact on
patient outcome.
Acknowledgements
None.
Financial support and sponsorship
None.
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Conflicts of interest
There are no conflicts of interest.
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