10. Qualitätsindikatoren – Peniskarzinom

Horenblas, 1993, Journal of Urology

Retrospective cohort study

n= 110

Netherlands

1956-1989

Follow-up

at least 2 ½ y

To establish a rational and uniform treatment protocol.

Grade 1-3

N0-N+

Clinical groin status

n= 66 cN0-patients

Median age

65 y (31-94 y)

cN0-patients

•  Surveillance (n= 57)

cN0-patients

• Lymph node dissection (n= 4)
• Lymph node dissection+ external beam radiation therapy (n= 1)
• External beam radiation therapy (n= 4)

N0

Regional recurrence

Surveillance: 5/57

Lymph node dissection: 0/4

Lymph node dissection+ external beam radiation therapy: 1/1

External beam radiation therapy: 1/4

Death from tumor

Surveillance: 2/57

Lymph node dissection: 0/4

Lymph node dissection+ external beam radiation therapy: 1/1

External beam radiation therapy: 1/4

We found a clear relationship among T category, grade and the probability of lymph node invasion. Patients with stage T1 tumors and stage T2, grades 1 and 2 tumors presented significantly less often with lymphatic invasion than those with other categories of disease and were less likely to have a regional recurrence after treatment of the primary tumor only. In these categories we recommend surveillance of the regional lymph nodes in patients who present with unsuspected nodes.

Ergebnisse nur für N0 dargestellt.

LoE 3

NOS 7/9

Hughes, 2010, European Urology

Retrospective cohort study

n= 117

Netherlands & United Kingdom

1956-2005

Median follow-up

44 mo (6-358 mo)

To establish the risk of lymph node metastasis in G2T1 disease.

G2T1

cN0= 105

cN1= 12

Median age

63 y (32–92 y)

Watchful waiting

n= 31 cN0-patients

Surgical staged

n= 74 cN0-patients

• iLND (n= 10)
• DSLNB (n= 64)

LN metastases

0/10 iLND

5/64 DSLNB

4/31 Watchful waiting

The overall risk of lymph node metastasis at initial

staging or during surveillance was 9% (9:105) in cN0-patients.

Deaths

2= Watchful waiting

1= cN1pN+ cohort (surgically staged)

We consider that in cN0 patients with G2T1 penile cancer, the risk of developing metastases during surveillance warrants surgical and potentially curative staging. The morbidity of prophylactic bilateral ILND is too great to justify a detection rate of 9%. Less morbid alternatives such as DSLNB are advisable in G2T1 disease.

LoE 3

NOS 7/9

Lont, 2003, Journal of Urology

Retrospective cohort study

n= 162

Netherlands

1956 – 1994 initial surveillance

1994-2001 DSNB

Median follow-up

Surveillance: 179 mo (60-541 mo)

DSNB:

56 mo (16-99 mo)

Evaluation of the clinical outcome of clinically node negative penile carcinoma

managed by surveillance or further diagnosed by DSNB with subsequent resection of LN metastases.

T2–3

G1-3

N0

M0

Mean age

Surveillance: 64.5 y

DSNB: 63.8 y

Initial surveillance

n= 85

DSNB

n= 68

3 y-DSS

Surveillance: 79% (95% CI 70-88%)

DSNB: 91% (95% CI 84-98%)

p= 0.04

3 y-OS

Surveillance: 66%

DSNB: 82%

Metastases

Surveillance

24%

Median-recurrence-free interval: 6 mo (1-24 mo)

DSNB

21%

DSNB sensitivity for occult metastases: 80%

Early detection of LN metastases by DSNB and subsequent resection in clinically node negative T2–3 penile carcinoma improves survival compared with a policy of surveillance.

LoE 3

NOS 8/9

Naumann, 2005, Onkologie

Retrospective cohort study

n= 16

Germany

1992-2003

Median follow-up

53.5 mo (9-146 mo)

To evaluate the risk of metastatic disease in patients with pT1 G2 squamous cell carcinoma of the penis.

pT1 G1-3

cN0-cN+

Mean age

61.5 y (36-87 y)

Early ILND

n= 10

Surveillance

n= 6

Early ILND

1 patient showed inguinal micrometastastes

1 patient with G3-tumor died of metastatic disease

Surveillance

3 patients recurrence

2/3 died of metastatic disease

The natural behaviour of pT1 G2 squamous penile carcinoma and its metastatic potential has been underestimated in recent literature.

Since morbidity after early ILND has markedly

decreased and its superiority over delayed ILND has been shown, we advocate the early modified inguinal lymph node dissection until strong prognostic factors for positive inguinal lymph nodes have been validated.

Ggf. Überschnei-dungen zwischen dem Patienten-kollektiv von Naumann 2006 oder Naumann 2008

LoE 3

NOS 7/9

Naumann, 2006, Urologe

Retrospective cohort study

n= 37

1995-2005

Follow-up

62 mo (22-162 mo)

The aim of this study was to evaluate the metastatic risk of T1 carcinoma and to compare it with that of T2 carcinoma.

T1-2

G1-3

N0-N+

30 Patienten mit unauffälligem inguinalen Lymphknoten-status

Mean age

61 y (34-84 y)

Prophylaktische ILND

n= 14

Surveillance

n= 16

Prophylaktische ILND

3/14 metastasierter Befall

Surveillance

8/16 unauffälliger Verlauf

7/16 inguinale Metastasen

Surveillance

Falsch-negative Rate cN0: 33%

Falsch-positive Rate bei suspektem Lymphknotenstatus: 43%

Keiner der G1-Tumore, aber alle der G3-Tumore haben unabhängig

vom Tumorstadium inguinale

Lymphknotenmetastasen entwickelt.

38% der G2-Tumore zeigten einen syn- oder metachronen Befall

der Leistenlymphknoten

Nichtmetastasierte Karzinome: 8 T1- und 8 T2-Tumore

The metastatic potential of T1 penile carcinoma has been underestimated in the recent literature. Tumor grading has substantially stronger impact on the metastatic risk in T1 and T2 penile carcinoma than tumor stage, indicating a surgical lymph node staging starting at the pT1G2 stage.

Ggf. Überschnei-dungen zwischen dem Patienten-kollektiv von Naumann 2005 oder Naumann 2008

LoE 3

NOS 5/9

Naumann, 2008, BJUI

Retrospective cohort study

n= 20

1996-2005

Mean follow-up

31.4 mo (11-83 mo)

To evaluate the metastatic risk of pT1 G2 squamous cell carcinoma of the penis.

pT1 G2

cN0-cN+

Clinical groin status

n= 16 cN0-patients

n= 4 cN+-patients

Mean age

65 y (39-84 y)

cN0

Surveillance

n= 11

cN0

ILND

n= 4

DSNB

n= 1

Nodal status of clinical cN0-patients

Surveillance:

6 pN+ (1 N1, 3 N2, 2 N3)

5 cN0

Clinical groin status had no significant effect on pathological nodal status (p= 0.582)

Metastatic risk

Overall: 50%

Clinical cN0 group: 44%

Recurrence and death

Surgical staging group: No recurrence or death

Surveillance group:

died because of

• Toxicity of neoadjuvant chemotherapy (n= 1)
• Progressive metastatic disease despite extensive surgical treatment and subsequent adjuvant chemotherapy (n= 2)

Side effects

Surgical staging group:

• Mild wound dehiscence (n= 2)
• Lymphocele (n= 1)
• Complexe wound healing failure (n= 2)
• Lymphorrhoea and recurrent lymphoceles (n= 2)

As the metastatic risk of pT1 G2 penile SCC

was 50% in this series of patients, and 44% in those with an initially negative groin,

surgical staging of inguinal lymph nodes is recommended in patients with pT1 G2 penile squamous cell carcinoma.

Ggf. Überschnei-dungen zwischen dem Patienten-kollektiv von Naumann 2005 oder Naumann 2006

Ergebnisse nur für cN0 dargestellt

LoE 3

NOS 4/9

Bermejo, 2007, Journal of Urology

Retrospective case serie

n= 10

1985-2000

Median follow-up

62 mo (48-84 mo)

To report the experience with surgical

consolidation for a select group of patients with clinically evident or pathologically proven lymph node involvement who initially demonstrated stable disease or an objective response to chemotherapy.

Tx-3

N1-3

M0-1

Median age

56 y (41-86 y)

Induction chemotherapy

• Paclitaxel, ifosfamide+ cisplatin
• Methotrexate, bleomycin+ cisplatin
• Paclitaxel+ carboplatin

Response

4/10 complete

1/10 partial

5/10 stable disease

5 y-OS

50%

Median survival (3 or fewer positive lymph nodes, n= 3)

23 mo (3-30 mo)

Toxicity

3/10 grade III nonhematological

toxicity, including 1 episode each of bleomycin toxicity, acute renal failure and deep venous thrombosis

Selected patients with metastatic penile cancer that show disease stabilization or a response to chemotherapy

should be considered for surgical consolidation to extend survival.

LoE 4

RoB 13/20

Chen, 2009, Japanese Journal of Clinical Oncology

Retrospective case serie

n= 5

2005-2009

Mean follow-up

24.2 mo (17-34 mo)

To evaluate the efficacy and adverse effects

of intra-arterial chemotherapy in the treatment of penile cancer

N0-N+

M0

Median age

61 y (48-79 y)

Inguinale LAD+ intra-arterial chemotherapy

Methotrexate (110 mg/

m2/day), mitomycin C (4.5 mg/m2/day), bleomycin (15 mg/

m2/day), cisplatin (35 mg/m2/day) and 5-fluorouracil

(1200 mg/m2/day)

n= 2

Response

2/2 partial

Time to relapse

4 mo and 8 mo

Adverse effects

• Anemia (grade 3)
• Anorexia (grade 1-2)

Our preliminary data indicated that a combination of intra-arterial chemotherapy, neoadjuvant chemotherapy and surgery may have the potential to achieve the goal in the treatment of penile cancer with negative lymph node.

LoE 4

RoB 12/20

Chiang, 2014, British Journal of Cancer

Retrospective case serie

n= 12

2005-2013

Follow-up

8-88 mo

To evaluate the role of intraarterial chemotherapy as first-line therapy for penile squamous cell carcinoma.

T1-3

N0-2

M0

N2= 3 patients

Age

48-89 y

5 patients with palpable inguinal node received surgery (partial/ total penectemy with LAD)

Neoadjuvant intraarterial chemotherapy (methotrexate, mitomycin C, bleomycin, cisplatin and 5-fluorouracil)

Tumor response

Overall: 83%

Node-negativ patients: 100%

Nodal invasion: 60%

Dead of disease (N2)

n= 2/3

Side effects

Grade 1 or 2 Anorexia: 7/12 (58%)

Grade 3

Haematological toxicity: 3/12

The preliminary results showed that intraarterial chemotherapy could be used as first-line therapy in any stage of penile squamous cell carcinoma before surgery.

LoE 4

RoB 11/20

Dickstein, 2016, BJU International

Retrospective case serie

n= 61

USA

1993-2011

Follow-up

5 y

Describe the clinical and pathological response rates,

survival, and predictors of survival when using contemporary

perioperative chemotherapy and surgical resection for patients with regionally advanced squamous cell carcinoma of the penis.

N0-3

N2= 20 patients

N3= 37 patients

Median age

60.6 y (24.5-81.4 y)

Induction regime

• TIP (Paclitaxel/ ifosfamide/ cisplatin chemotherapy)
• Carboplatin/ paclitaxel
• 5-fluorouracil/ cisplatin
• methotrexate/ bleomycin/ cisplatin

Objective response

39 (65%)

Median OS

N2: 35.8 mo (HR 0.87, 95% CI 0.24-3.13) p= 0.83

N3: 17.3 mo (HR 1.22, 95% CI 0.37-4.10) p= 0.743

Recurrence-Free-Survival

N2: 35.8 mo (HR 0.82, 95% CI 0.23-2.95) p= 0.763

N3: 10 mo (HR 1.47, 95% CI 0.44-4.85) p= 0.531

Contemporary chemotherapy resulted in clinically significant responses among patients with regionally advanced penile cancer.

Patients with resectable inguinal and pelvic lymph nodes underwent consolidative LAD after completing chemotherapy

LoE 4

RoB 12/20

Djajadiningrat, 2015, Clinical Genitourinary Cancer

Clinical trial

n= 26

2008-2012

Netherlands

Median follow-up

30 mo (6-17 mo)

To evaluate response, toxicity, PFS and disease-specific survival in patients with advanced

squamous cell carcinoma of the penis treated with neoadjuvant

taxane-based combination chemotherapy.

rTx, T2, T4

N0, N2, N3

N2= 3 patients

N3= 15 patients

Median age

61 y (35-73 y)

4 courses of TPF (docetaxel, cisplatin and 5-fluorouracil)

Overall response

60% (CI 95% 39-79%)

Median PFS

7 mo (95% CI 1.9-17.1 mo)

Median OS

10.1 mo (95% CI 6.7-28.1 mo)

Median disease-specific survival

10.3 mo (95% CI 8- ∞ mo)

Toxicity

26/26

Grade 4: 2

Grade 3: 14

Despite a fairly good response percentage, survival was disappointing at the expense of considerable toxicity.

Different procedures after chemotherapy (partial/

total penectomy, inguinal/pelvic dissection and

radiation therapy)

LoE 3

RoB 19/20

Joshi, 2018, JAMA Oncology

Retrospective cohort study

n= 1123

2004-2014

United States of America, Puerto Rico

To determine temporal trends in use of chemotherapy for patients with lymph node positive penile cancer without metastasis and to evaluate outcomes between those who did or did not receive LND, chemotherapy, and radiotherapy.

G1-4

N1-3

Age range

50-75 y

66.8% underwent LAD

LAD with or without chemotherapy or/and radiotherapy

Multivariable model predicting use of chemotherapy

N2: OR 1.54 (1.08-2.19) p= 0.02

N3: OR 2.15 (1.52-3.04) p< 0.001

Multivariable OS analysis

N2: HR 1.44 (1.17-1.78) p= 0.001

N3: HR 1.93 (1.52-2.45) p< 0.001

LAD: HR 0.64 (0.52-0.78) p< 0.001

Chemotherapy: HR 1.01 (0.8-1.26) p= 0.95

Median OS

LAD

28.8 mo (95% CI 24-40.3 mo)

LAD+ Chemotherapy

44.6 mo (95% CI 23.5-114.6 mo)

LAD+ Chemotherapy+ Radiotherapy

37.2 (95% CI 20.7-68.1 mo)

N2/N3 subgroups

Survival

Chemotherapy: HR 0.91 (95% CI 0.71-1.18) p= 0.49

Radiotherapy: HR 0.88 (95% CI 0.71-1.10) p= 0.26

Chemoradiotherapy: HR 0.97 (95% CI 0.88-1.07 p= 0.53)

LND+ Chemotherapy: p= 0.77

LND+ Radiotherapy: p= 0.99 

Receipt of LAD, but not chemotherapy or radiotherapy, is associated with overall survival.

Unklar, ob LAD sich nur auf inguinale LAD bezieht

LoE 3

NOS 5/9

Leitje, 2007,

European Urology

Retrospective case serie

n= 20 Netherlands

1972-2005

Median follow-up

23 mo (1-134 mo)

To assess the value of neoadjuvant

chemotherapy in 20 patients with irresectable penile

carcinoma treated at our institute.

T1-T4

N0-N3

Mean age

62 y (35-79 y)

Neoadjuvant therapies

until 1985 Single-agent therapy with bleomycin

1986-1999 Combination chemotherapy

with bleomycin, vincristin and methotrexate

1999-2001

Combination therapy of

5-fluorouracil and cisplatin

Since 2001

Cisplatin, bleomycin and methotrexate

5 y-OS

32% (95% CI 17-62%)

No correlation beetween survival and:

• T category (p= 0.75)
• N category (p= 0.85)
• Tumor differention (p= 0.65)
• Age (p= 26)

Responder

9/20 (2 complete, 7 partial)

Toxicity

Death: 3

Severe toxicity: 4

Side effects

Grade 1 and 2: Nausea, fatigue, Grade 1 or 2: Alopecia

These results suggest that neoadjuvant

chemotherapy is a valuable treatment option for patients with irresectable

penile carcinoma, which is otherwise considered incurable. Surgery

should be performed only in patients showing clinical response to

chemotherapy because prognosis for nonresponding patients who underwent surgery was dismal and local control was not improved.

Fünf verschiedene Therapieformen von 1972-2005, wobei die Ergebnisse für alle durch-geführten neoadjuvanten Therapien berichtet werden.

Surgery after chemotherapy were inguinal/ pelvic LAD and partial and total penectomy

LoE 4

RoB 15/20

Mitropoulos, 1994, Journal of Urology

Prospective case serie

n= 13

Greece

1990-1992

Follow-up:

11-38+ mo

Invastigate the antitumor activity and toxicity of cisplatin and interferon-alpha 2B as the primary treatment of penile carcinoma.

T2-3

M0

N0-3

Median age

62 y (27-74 y)

Surgery planned

9/13 Penectomy + node dissection

20 mg/m² cisplatin intravenously and 5 x 10(6) μ/m² interferon-alpha 2B subcutaneously daily for 5 consecutive days

N2 (n= 1)

• Partial penectomy & node dissection
• Partial response
• Disease-free after 22 mo

N3 (n= 1)

• Partial penectomy & node dissection
• Non-responder
• Died of metastatic disease (11 mo)

Toxicity

• Flu-like symptoms (13/13)
• Haematological toxic effects (5/12)
• Renal complication rate (3/13)

Primary treatment with cisplatin and interferon-alpha 2B induced responses in 75% of 12 patients with penile carcinoma and allowed for a less radical operation than originally scheduled.

Unklar, ob „node dissection“ sich nur auf inguinale LAD bezieht

LoE 4

RoB 16/20

Necchi, 2017, Clinical Genitourinary Cancer

Retrospective three arms cohort study

n= 201

12 centers Europe, USA & Canada

1990 onwards

Evaluate the impact of neoadjuvant chemotherapy alone or in conjunction with radiotherapy in patients with lymph node

positive disease.

T1-4

N0-3

Median age

67 y (35-87 y)

HPV-: 38

HPV+: 8

Neoadjuvant chemotherapy

n= 94

N2= 20 (21.3%)

N3= 45 (47.9%)

Adjuvant chemotherapy

n= 78

N2= 29 (37.2%)

N3= 19 (24.4%)

Neoadjuvant & adjuvant chemotherapy

n= 21

N2= 8 (38.1%)

Median relapse-free survival

Neoadjuvant

7.7% (95% CI 6.4-9.8%)

Adjuvant

32.8% (95% CI 9.7-132.7%)

Both

11.1% (95% CI 9.5-24.3%)

Median OS

Neoadjuvant

17.1% (95% CI 12.5-21.5%)

Adjuvant

105.3% (95% CI 19.8%-NE)

Both

18.5% (95% CI 11.8-30.2%

Relapse-Free Survival (N2)

HR 0.78 (95% CI 0.48-1.29)

OS (N2)

HR 0.87 (95% CI 0.50-1.52)

Substantial uncertainties still exist regarding the indications for

perioperative chemotherapy and the net benefit of administering

multimodal treatment compared to surgery alone in patients with

advanced penile squamous cell carcinoma and high-risk features, namely those with pelvic or bilateral lymph node involvement.

Unklar, ob LAD sich nur auf inguinale LAD bezieht

LoE 3

NOS 6/9

Nicolai, 2016,

Clinical Genitourinary Cancer

Retrospective cohort study

n= 47

2004-2012

Follow-up

22 mo (17-42 mo)

Evaluation of

the efficacy of a combination of taxane, cisplatin and 5-fluorouracil in neoadjuvant and adjuvant settings.

N2-3

ECOG 0-1

Neoadjuvant

Taxane, cisplatin,and 5-fluorouracil

n= 28

Adjuvant

Taxane, cisplatin,and 5-fluorouracil

n= 19

Alive and maintained progression free

Neoadjuvant

28.6% (95% CI 15.2-47.3)

Median time: 17 mo (15-25 mo)

Adjuvant

52.6% (95% CI 31.8-72.6)

Median time: 42 mo (9-68 mo)

Relapses

Neoadjuvant

42.8% (95% CI 23.2-63.7)

Median time: 8 mo (5-10)

Adjuvant

42.1% (95% CI 23.2-63.7)

Median time: 8 mo (9-10 mo)

Dead of Disease:

Adjuvant

42.1%

Median time: 15 mo (12-23 mo)

Neoadjuvant

32.1%

Median time: 10 mo (4-16 mo)

The taxane, cisplatin and 5-fluorouracil regimen is well tolerated and compares with other regimens in terms of activity and efficacy in the neoadjuvant setting.

The role of perioperative treatment in these patients remains controversial.

LoE 3

NOS 8/9

Otto, 2003, Urologe

Case serie

n= 15

Mean follow-up

15 mo

Beschreibung der Therapie des fortgeschrittenen Peniskarzinoms.

T3-4

Mean age

74 y

Neoadjuvante Chemotherapie

2–4 Kurse Polychemotherapie mit Cisplatin, Methotrexat und Bleomycin, 3 Wochen später Tumorresektion

Partielle Remission: 3

Tod: 4 (tumorbedingt)

Fernmetastasen: 5

Nebenwirkungen:

11/15 Grad 2 gastrointestinal

9/15 Grad 3 hämatologisch

3/15 Grad 4 hämatologisch

Die Ergebnisse belegen, dass die Kombination von Chemotherapie und ausgedehntem operativen Vorgehen einerseits das Überleben des alten Patienten nicht nachhaltig beeinflusst, andererseits die Lebensqualität des symptomatischen Patienten entscheidend verbessert, was vorrangig auf die operative Behandlung zurückzuführen ist.

Keine Aussagen zum Node-Status

LoE 4

RoB 7/20

Pagliaro, 2010, Journal of Clinical Oncology

Clinical trial

(phase 2 study)

n= 30

2000-2008

Median follow-up

34 mo (14-59 mo)

Determining the response rate, time to progression and OS of neoadjuvant chemotherapy

among patients with bulky adenopathy.

N2-N3

M0

Median age

57.5 y (24-78 y)

n= 22 complete chemotherapy and then LAD

Neoadjuvant treatment

175 mg/m² paclitaxel intravenously

over 3 hours day 1; ifosfamide 1,200 mg/m² on days 1 to 3; and cisplatin

25 mg/m² on days 1 to 3

Median time to progression:

8.1 mo (95% CI 5.4-50+)

(20/30 patients died)

OS

17.1 mo (95%

CI 10.3-60+)

The neoadjuvant regimen of paclitaxel, ifosfamide, and cisplatin induced clinically meaningful responses in patients with bulky regional lymph node metastases from penile cancer.

LoE 3

RoB 17/20

Pizzocaro, 2009, European Urology

Prospective case serie

n= 6

2004-2006

Italien

To evaluate the therapeutic activity of taxanes in combination with cisplatin-fluorouracil for salvage of primarily unresectable or relapsed nodal

metastases from squamous cell carcinoma of the penis.

G1-3

T1-3

N0-3

Age

44-74 y

Neoadjuvant treatment

Paclitaxel, cisplatin, and 5-

fluorouracil

No evidence of disease

3/6

Follow-up: 25, 27 and 46 mo

Dead of disease

3/6

Follow-up: 4, 6 and 11 mo

Toxicity

1/6 patients: severe nausea and vomiting, hematologic toxicity

Paclitaxel, cisplatin, and 5-fluorouracil chemotherapy for unresectable or recurrent nodal metastases from squamous cell carcinoma of the penis is promising, and the standard four courses of therapy are to be completed in responding patients.

LoE 4

RoB 17/20

Pizzocaro, 1988, Acta Oncologica

Retrospective

case series

n= 17

1979-1985

Italien

Median follow-up

42 mo (18-102 mo)

To describe the results of adjuvant and neoadjuvant treatment with vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis.

Age

Adjuvant:  21-74 y (median: 5 5y)

Neoadjuvant: 40-62 y

Neoadjuvant with 12 weekly

courses of vincristine, bleomycin and methotrexate

n= 5

Adjuvant

vincristine, bleomycin and methotrexate

n= 12

Neoadjuvant group

Partial remission: 3

Minor remission: 2

Free of disease: 3 (20, 27 and 72 mo)

Death: 2 (1 and 4 mo)

Adjuvant group

11/12 free of disease

1/12 relapsed (16 mo)

Survival

3= free of disease (20, 27 and 72 mo)

2= died (1 and 4 mo)

Toxicity

1= Myelosuppression

2= Lung fibrosis

4= Hyperpyrexia >38°C

8= Hyperpigmentation

1= Stomatitis

Our results suggest that this low-dose combination chemotherapy is also efficient in squamous cell carcinoma of the penis.

N-Status unklar

LoE 4

RoB 9/20

Protzel, 2009, Urologia Internationalis

Systematic review

1966-2008

To review the available literature concerning chemotherapy

regimens for penile cancer with response rates and survival when reported.

n= 7 studies with neoadjuvant setting

Neoadjuvant treatment

• Vinblastine, Methrotrexate, Bleomycin (n= 2)
• Cisplatin, Methotrexate, Bleomycin (n= 2)
• Paclitaxel+ Carboplatin (n= 1)
• Paclitaxel, Cisplatin, Ifosfamide (n= 1)
• Paclitaxel, Cisplatin, 5-Fluoruracil (n= 1)
• Cisplatin, Irinotecan (n= 1)

Monochemo-therapies,  polychemo-therpies and adjuvant chemo-therapies

Cisplatin (20-30 mg/m2)

Methotrexate (200 mg/m2)

Bleomycin (15 mg/m2)

Response: 6/10

Treatment-related death: 2/10

Cisplatin (20 mg/m2)

Methotrexate (200 mg/m2)

Bleomycin (10 mg/m2)

Response: 3/3 stable disease

Treatment-related death: 0/3

Median survival: 7 mo

Vinblastine,

Methotrexate,

Bleomycin

Response: 6/10

Treatment-related death: 1/10

Paclitaxel+ Carboplatin

Response: 3/3

Paclitaxel, Cisplatin, Ifosfamide

Response: 4/5

Complete response: 3/5

Median survival: 30 mo

Paclitaxel, Cisplatin, 5-Fluoruracil

Response: 3/3

Complete response: 2/3

Median survival: 11 mo

Cisplatin, Irinotecan

Response: 6/7

Complete response: 1/7

Neoadjuvant treatment should be given in all cases of fixed lymph node metastasis and possibly for all patients with suspected

lymph nodes metastasis. Adjuvant treatment should be proven with new regimens, which might also be able to improve the poor prognosis of patients with distant metastasis.

LoE 3

ROBIS high

Tang, 2018, Urologic Oncology

Case report

n= 3

Follow-up

9-12 mo

Describe an aggressive approach for isolated retroperito- neal recurrences using a multimodal approach with systemic chemotherapy followed by consolidative lymph node dis- section in a small cohort of patients

PT3N1M0

PT2N3M0

PT3N3M0

Age

61-71 y

Postchemotherapy

3 cycles of paclitaxel, ifosfamide, and cisplatin

Response

Complete: 1/3

Partial: 2/3

No Evidence of Disease

3/3

It must be appreciated that such an aggressive multimodal strategy may only prove beneficial to a subset of penile cancer patients, which should be encompassed within our important therapeutic education and discussions.

Bezieht sich auf die Behandlung von Patienten, die bereits einen Rückfall haben

LoE 4

RoB 10/20

Theodore, 2008, Annals of Oncology

Prospective phase II study

n= 28

2004-2006

To determine efficacy and feasibility of the combination regimen irinotecan and cisplatin in patients with cisplatin advanced penile cancer.

T3-4

N1-3

M1

Median age

55 y (36-77 y)

WHO PS: 0-2

Neoadjuvant therapy

Combination of irinotecan (60 mg/m²) on days 1, 8 and 15 and cisplatin (80mg/m²) every 28 days

n= 7 (3/7 underwent a lymphadenectomy after chemotherapy)

Neoadjuvant setting

Overall response rate

2/7 (28.6%, 95% CI

3.7% to 71%)

• 1/7 complete
• 1/7 partial

Overall

Clincal adverse events

Grade 4:

• Hypotension (n= 1)
• Cardiac (thrombosis) (n= 1)
• Fatigue (n= 1)
• Neutropenic infection (n= 2)
• Pulmonary (embolus) (n= 1)
• Haemorrhage (n= 1)

Grade 3:

• Hypotension (n= 1)
• Cardiac (thrombosis) (n= 2)
• Fatigue (n= 2)
• Neutropenic infection (n= 1)
• Pulmonary (embolus) (n= 1)
• Diarrhoe (n= 3)

The study fails to demonstrate a response rate significantly >30%.

Unklar, welcher N-Status bei den Patienten, die neoadjuvant therapiert wurden und in welchem Bereich die LAD durchgeführt wurde.

LoE 3

RoB 14/20

Zou, 2014, Journal of Cancer Research & Clinical Oncology

Retrospective case serie

n= 24

China

2001-2010

Mean follow-up

50.1 mo (7-122 mo)

To evaluate the efficacy of preoperative neoadjuvant

chemotherapy combined with a BMP regimen including

bleomycin, methopterin and cisplatin

for treating advanced penile cancer patients.

T1-3

pN3

Mean age

53.4 y (38-71 y)

Neoadjuvant chemotherapy followed by surgery (lymphadenectomy and/or (partial) penectomy) + chemotherapy

n= 15

Neoadjuvant + surgery group

Response

Complete: 0%

Partial: 62.5%

Progressive disease: 8.33%

Recurrence

3/14 inguinal lymph node

0/14 local

Overall

Adverse events

• Bone marrow depression (83.3%)
• Oral mucous damage (45.8%)

Surgery related:

• Lower extremity lymphedema (86.7%)
• Delayed wound healting (66.7%)
• Perineal edema (6.67%)
• Dysuria (6.67%)

Neoadjuvant chemotherapy combined with a bleomycin, methopterin and cisplatin regimen followed by surgery is beneficial to patients with advanced penile cancer.

Ergebnisse sind nur die PICO-Frage betreffend dargestellt.

LoE 4

RoB 15/20