Rational treatment delivery in clinical stage I and II testicular germ cell tumours ... · 2017. 1. 10. · Rajpert-De Meyts E, et al., Lancet 2016; 387(10029):1762-1774 Roughly 75%

RATIONAL TREATMENT DELIVERY IN

CLINICAL STAGE I AND II TESTICULAR

GERM CELL TUMOURS (INCLUDING

LONG-TERM TOXICITIES)

Andrea Necchi

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

‘…Incidence rates continue to increase in

most countries worldwide, more markedly in Southern Europe and Latin America.

Mortality from TC shows a different pattern, with higher rates in some countries of

medium to high Human Development Index (HDI)….’

Source: International Agency for Research on Cancer, GLOBOCAN 2008. Incidence is reported per 100 000 men per year

Reprinted from Eur Urol 65(6), Znaor A, et al., International variations and trends in testicular cancer incidence and mortality,1095–106

Copyright 2014, with permission from Elsevier

Median Age

25 > 35

32 > 39

23 > 29

#2,482 Pts, 1976-2010,

2 German Urologic Centres

SHIFTING CLINICAL PRESENTATION

OF TESTICULAR GERM CELL TUMOURS

Reprinted from Urol Oncol, 2014: 32 (1) Ruf CG, et al., Changes in epidemiologic features of testicular germ cell cancer: Age at diagnosis and relative

frequency of seminoma are constantly and significantly increasing, 33.e1-33e6. Copyright 2014, with permission from Elsevier

Rajpert-De Meyts E, et al., Lancet 2016; 387(10029):1762-1774

Roughly 75% of all testicular germ cell tumours (80% of seminomas and 60% of

non seminomas) are detected in clinical stage I

Orchiectomy alone cures 80% of seminomas and 70% of non-seminomas, and

standard care has increasingly shifted to active surveillance

Patients with CSI seminomas have a 13–19% rate of relapse

Primary pathological risk factors are poorly defined

Patients with CSI nonseminomas have a 30% risk of relapse, which may

necessitate treatment

However, one key risk factor (LVI) has been defined

CLINICAL STAGE I (CSI)

TESTICULAR GERM CELL TUMOUR

RISK FACTORS FOR RELAPSE IN

CLINICAL STAGE I NONSEMINOMA:

ROLE OF VASCULAR INVASION

Feldman, DR, J Clin Oncol 2014 ; 32(34): 3797-3800. Reprinted with permission. ©2014 American Society of Clinical Oncology. All rights reserved

Vergouwe Y, et al., J Clin Oncol 2003; 21(22):4092-9. Reprinted with permission. ©2003 American Society of Clinical Oncology. All rights reserved

RISK FACTORS FOR RELAPSE

In Clinical Stage I Seminomas have

not been validated yet - 1

Pooled analysis

638 pts from 4 institutions (PMH, RMH,

DATECA, RLH)

Median follow-up: 7 years

121 patients relapsed

5 year relapse-free rate of 82.7%

On multivariate analysis

Tumour size

Rete Testis invasion

Warde P, et al., J Clin Oncol 2002, 20(22):4448-4452 Reprinted with permission © (2002) American Society of Clinical Oncology. All rights reserved.

Retrospective, population-based study of Danish patients diagnosed with

stage I seminoma between 1984 and 2008 and followed for 5 years

(n = 1,954)

From 2000 to 2006, a total of 1,384

Norwegian and Swedish patients were

included in a retrospective, population-

based study

Tandstad T, et al., J Clin Oncol 2011; 29(6): 719-725. Reprinted with permission © 2011, American Society of Clinical Oncology. All rights reserved

Reprinted from European Urology (2014); 66(6), Mortensen MS, et al., A Nationwide Cohort Study of Stage I Seminoma Patients Followed on a Surveillance

Program:1172-8. by European Association of Urology. Copyright 2014, with permission from Elsevier


In Clinical Stage I Seminomas have not been validated yet - 2

2007-2010

897 patients included

in a prospective

population-based

SWENOTECA risk-

adapted treatment

protocol


In Clinical Stage I Seminomas have not been validated yet - 3

….although new available data in 2016 did support the reliability of tumour size and

Rete Testis invasion

Tandstad T, et al.,Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing

patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) Ann Oncol 2016; 27(7):1299–304

Copyright © 2016 by permission of Oxford University Press on behalf of the European Society for Medical Oncology

Author, year N Treatment(s) Median F/U Univariate Multivariate

Warde, 2002 638 Surveillance 7.0 years

• Tumour size >4cm

• Rete testis invasion

• Vascular invasion



Kamba, 2010 425

Surveillance

Radiotherapy

Chemotherapy

4.4 years


• Postorchiectomy

management


• Postorchiectomy

management

Chung, 2010 687 Surveillance 3.8 years • Tumour size (continuous) • No significant factor

Tandstad, 2011 512 Surveillance 5.2 years • No significant factor • No significant factor

Soper, 2012 502

Surveillance

Radiotherapy

Chemotherapy

N.R.

• Tumour size



• No significant factor

Mortensen, 2013 1,822 Surveillance 15.4 years



• BHCG >200 IU/l




• BHCG>200 IU/l

Aparicio, 2014 744Surveillance

Chemotherapy6.6 years


• pT staging



• Tumour size

(continuous)

Tandstad, 2016 897Surveillance

Chemotherapy5.6.years





DILEMMAS IN IDENTIFYING RISK

FACTORS IN CSI SEMINOMA

Updated in 2016 from Aparicio J, et al., Ann Oncol 2014

3 RISK-ADAPTED SPANISH TRIALS

JOINTLY ANALYSED:

N=744 PTSDFS: Surveillance (pink) vs. adjuvant CBDCA (green)

Nomogram built upon N=396 patients

Managed by surveillance only

This model needs to be validated

for use outside of clinical trials

Aparicio J, et al., Prognostic factors for relapse in stage I seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the

Spanish Germ Cell Cancer Group (SGCCG) Ann Oncol 2014;25(11):2173–8


PROMISING NEW BIOMARKERS

ON THE HORIZON: MIR 371A-3P IN GCT

Dieckmann K-P, et al., Serum Levels of MicroRNA miR-371a-3p: A Sensitive and Specific New Biomarker for Germ Cell Tumours. Eur Urol (2016),

http://dx.doi.org/10.1016/j.eururo.2016.07.029. © 2016 European Association of Urology. Published by Elsevier B.V. This is an open access article under

the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Benchmark marker decline:

HCG: 24 to 36h

AFP: 7 days

Clinical Stage II

Clinical Stage III

Relapsing disease

CHANGES IN MIR-371A-3P LEVELS IN

INDIVIDUAL PATIENTS WITH SYSTEMIC DISEASE

Postoperatively and during the course of chemotherapy

Dieckmann K-P, et al., Serum Levels of MicroRNA miR-371a-3p: A Sensitive and Specific New Biomarker for Germ Cell Tumours. Eur Urol (2016),

http://dx.doi.org/10.1016/j.eururo.2016.07.029. © 2016 European Association of Urology. Published by Elsevier B.V. This is an open access article under

the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

See also Syring I, et al., J Urol 2015, for additional data

But in high-volume

centres relapse rate

after RPLND can be

much lower

THE DILEMMA OF CSI

From N Engl J Med, Hanna H, Einhorn LH, Testicular Cancer — Discoveries and Updates, 371:2005-2016.

Copyright ©2014. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

NATIONWIDE COHORT STUDY OF

STAGE I SEMINOMA PATIENTS

Followed on a surveillance programme

Danish cohort, seminoma, 1984-2008

N=1,954 patients, 15-y DSS=99.3%

Surveillance is a rational choice in most CSI seminomas

The era of routine adjuvant radiation therapy in CSI seminoma has passed

Efficacy, ideal duration, and late-effect profiles of adjuvant carboplatin are

unknown

Mortensen MS, et al., Eur Urol 2014;66(6):1172-8

1 cycle of CBDCA AUC 7 is the standard

chemotherapy option

Published in THE LANCET, Vol 366, No 9482, Oliver RTD, et al., “Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I

seminoma: a randomised trial” pp 293-300. Copyright Elsevier (2005)

ADJUVANT THERAPY IN CSI

SEMINOMA


SEMINOMA

Risk-adapted approach -1

Aparicio J, et al., J Clin Oncol 2011, 29(35):4677-4681. Reprinted with permission. © (2011) American Society of Clinical Oncology. All rights reserved.

From 2004 to 2008, 227 patients were included in a Spanish multicentre study

Median follow-up: 34 months

15 relapses (9.8%) among patients on surveillance and 1(1.4%) among those treated with carboplatin

3-year DFS rate: 88.1% (95%CI, 82.3% to 93.9%) for surveillance and 98.0% (95% CI, 94.0% to 100%) for

adjuvant chemotherapy


SEMINOMA

Risk-adapted approach -2

Years or treatment: 2007-2010

897 patients included in a prospective population-based SWENOTECA risk-adapted treatment protocol

CBDCA AUC7x1 or Surveillance based on tumour size >4cm and Rete testis invasion

Tandstad T, et al., Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing

patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) Ann Oncol 2016; 27(7):1299–304


LV-

LV+

Patterns of relapse Retrospective study including data from

2,483 clinical stage I (CSI) patients

1,139 CSI nonseminoma managed with

active surveillance, with the majority

treated between 1998 and 2010

Relapses occurred in 221 of 1,139

(19%) patients, 44% LVI-positive

patients, 14% LVI-negative patients,

and in 38% patients with unknown LVI

status

10% of relapsed were IGCCCG

Intermediate or Poor Prognosis

Only 5 disease/treatment-related

deaths

ACTIVE SURVEILLANCE IN CSI

NONSEMINOMATOUS GCT-1

Kollmannsberger C, et al., J Clin Oncol 2015, 33(1): 51-57

Reprinted with permission. © (2015) American Society of Clinical Oncology. All rights reserved.

Daugaard G, et al., J Clin Oncol 2014, 32(34); 3817-3823

Reprinted with permission. © (2014) American Society of Clinical Oncology. All rights reserved.

N=1,226 patients from a Danish population-based study 1984-2007

30.6% Risk of Relapse at 5-years

5-y risk of relapse without risk factors: 12%

ACTIVE SURVEILLANCE IN CSI

NONSEMINOMATOUS GCT-2

LARGEST ACTIVE SURVEILLANCE

TRIALS IN CSI NONSEMINOMA

Kovac E & Stephenson AJ, Urol Clin N Am 2015; 42(3):299-310

StudyNo.

Patients Relapses (%)

Median

follow-up (mo)

Median time to

relapse (mo)

% systemic

relapse*

GCT deaths

(%)

Read et al,24 1992 373 100 (27) 60 3 (1.5-20) 39 5 (1.3)

Daugaard et al,37 2003 301 86 (29) 60 5 (1-171) 66 0

Freedman et al,34 1987 259 70 (32) 30 NR 61 3 (1.2)

Colls et al,32 1999 248 70 (28) 53 NR 73 4 (1.6)

Francis et al,33 2000 183 52 (28) 70 6 (1-12) 54 2 (1)

Gels et al,35 1995 154 42 (27) 72 4 (2-24) 71 2 (1)

Sharir et al,36 1999 170 48 (28) 76 7 (2-21) 79 1 (0.5)

Sogani et al,25 1998 105 27 (26) 136 5 (2-24) 37 3 (3)

Duran et al,39 2007 305 77 (25) NR 7 26 2 (0.7)

Tandstad et al,30 2009 350 44 (13) 56 8 27 0

Kollmannsberger et al,382010 223 59 (26) 52 NR NR 0

Kollmannsberger et al,9 2015 1139 221 (19) 62 6 (4-8) NR 3 (<1)

German randomised phase III study

N=382, between 1996 and 2005

Albers P, et al., J Clin Oncol 2008, 26(18): 2966-2972. Reprinted with permission. © (2008) American Society of Clinical Oncology. All rights reserved.

ADJUVANT CHEMOTHERAPY

OPTION FOR CSI NONSEMINOMA

BEP x 1 cycle is the standard

N=517 patients received adjuvant BEP

chemotherapy

Prospective, binational (Norwegian,

Swedish), population-based, risk-

adapted study

Patients with LVI > BEP x 1

Patients without LVI > BEP x 1 vs.

surveillance

5-y relapse-rate: 3.2% and 1.6%

5-y cause-specific survival: 100%

Tandstad T, et al., One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group. Ann

Oncol 2014;25(11):2167–72. Copyright © 2014 by permission of Oxford University Press on behalf of the European Society for Medical Oncology

ADJUVANT CHEMOTHERAPY

OPTION FOR CSI NONSEMINOMA

BEP x 1, mature data from a risk-adapted approach

Single-institution retrospective study

N=322 consecutive CS1

NSGCT patients, between 1985 and 1995

ADJUVANT RPLND FOR CSI

NONSEMINOMA SHOULD BE CONFINED

TO HIGH-VOLUME CENTRES -1

Reprinted from Eur Urol, 58(6), Nicolai N, et al., Retroperitoneal lymph node dissection with no adjuvant chemotherapy in clinical stage I

nonseminomatous germ cell tumours: long-term outcome and analysis of risk factors of recurrence. 912–8. Copyright 2010, with permission from Elsevier

Results of recurrence analysis by multivariable

logistic regression model*

Kovac E & Stephenson AJ, Urol Clin N Am 2015; 42(3):299-310

ADJUVANT RPLND FOR CSI

NONSEMINOMA SHOULD BE CONFINED TO

HIGH-VOLUME CENTRES -2

No.

Patients PSII (%)

% teratoma in

retroperitoneum

% relapse

PSI

% relapse

PSII

% adjuvant

chemotherapy

GCT

deaths (%)

Donohue et al,55 1993 378 113 (30) 15 12 34 13 3 (0.8)

Hermans et al,56 2000 292 67 (23) NR 10 22 12 1 (0.3

Nicolai et al,51 2010 322 61 (19) NR 12 32 NR 5 (1.6)

Stephenson et al,8 2005 297 83 (28) 15 6 19 15 0

Williams et al,57 2009 76 37 (49) NR 5 11 NR 0

Albers et al,58 2008 173 31 (19) NR 9 NR 19 0

Richie et al,59 1990 99 35 (35) NR 6 15 15 0

Largest reported series of primary RPLND

THE DILEMMA OF RISK-ADAPTED

VS. NON RISK-ADAPTED APPROACH IN

CSI NONSEMINOMA -1

Oldenburg J, et al., Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular

cancer. Ann Oncol 2015;26(5):833–8. Copyright © 2016 by permission of Oxford University Press on behalf of the European Society for Medical Oncology

Feldman DR, J Clin Oncol 2014; 32(34): 3797-3800. Reprinted with permission, ©2014 American Society of Clinical Oncology. All rights reserved.

THE DILEMMA OF RISK-ADAPTED

VS. NON RISK-ADAPTED APPROACH IN

CSI NONSEMINOMA -2

Survival probability is

lower for CSI patients

harbouring TMT in the

orchiectomy specimen

Reprinted from J Urol, 196(1), Giannatempo P, et al., Treatment and Clinical Outcomes of Patients with Teratoma with Somatic-Type Malignant

Transformation: An International Collaboration, 95–100. Copyright 2016, with permission from Elsevier

PRIMARY RPLND MAY BE

RECOMMENDED IN SPECIAL CASES WITH

HIGH-RISK CSI NONSEMINOMA

Details do matter in

orienting the therapeutic

choice for CSI GCT

CSI, LONG-TERM SIDE EFFECTS

OF TREATMENTS

Hanna NM & Einhorn LH, J Clin Oncol 2014, 32(28): 3085-3092

Reprinted with permission. © (2014) American Society of Clinical

Oncology. All rights reserved.

Late toxicity, second cancers

Active RxDx Years

>20

Imaging (CT scans, chest X-ray, etc.)

Acute toxicity (haematologic,

neurotoxicity, ototoxicity, DVT, sterility, etc.)

Follow-up

Radiological assessments

GERM CELL TUMOURS: BURDEN

OF POTENTIALLY HARMFUL INTERVENTIONS

IN THE TREATMENT TIME COURSE

7.4 6.7 7.5

17.7 16.7

0

5

10

15

20

Surgery Radiotherapy Cisplatin ≤850 mg Cisplatin >850 mg Cisplatin/pulmsurg

Study

(no. of patients)

Year of

diagnosis

Median fu

(range), yTreatment characteristics

Risk of CAD

(95% CI)

Statistical

methodComments

Huddart et al. (992)

[52]

1982-1992 10 (0-20) Surgery only

Radiotherapy

Chemotherapy

CT and RT

1.0 (reference)

2.4 (1.0-5.4)

2.6 (1.2-5.8)

2.8 (1.1-7.1)

RR “Cardiac event” as measured end

point.b Adjusted for age.

Van den Belt-

Dusebout et al.

(2,339) [50]

1965-1995 18 (5-38) Surgery only

RT infradiaphragmatic (inf)

RT mediastinum (med)

Chemotherapy

CT and RT inf

CT and RT med

0.8 (0.5-1.2)

0.7 (0.6-0.9)

1.6 (1.1-2.4)

1.2 (0.8-1.6)

1.3 (0.7-2.3)

2.3 (1.2-3.9)

SIR CAD >5 years after diagnosis.

CAD data were obtained from

medical records and thorough

questionnaires sent to patients’

general practitioners. Compared

with age-matched controls.

Haugnes et al. (990)

[51]

1980-1994 19 (13-28) Surgery only

Radiotherapy

Chemotherapy (CVB alone)

Chemotherapy (BEP alone)

CT and RT

1.0 reference

2.1 (0.8-5.4)

2.0 (0.7-6.1)

5.7 (1.9-17.1)

5.3 (1.5-18.3)

HR CAD >2 years after diagnosis.

Fatal events excluded. All self-

reported CAD events validated by

use of medical records. Adjusted

for age.

Lauritizen et al.

(4,697) [53]

1984-2007 15 (IQR 10-

21)

Surveillance

Chemotherapy (BEP)

RT, curative

RT, adjuvant

1.0 reference

1.6 (1.1-2.3)

0.7 (0.4-1.4)

1.0 (0.5-2.0)

HR CAD data from national registries

and hospital records. Adjusted for

age and tobacco use.

CAD

Lung disease

(% Pts)

RISK OF CORONARY ARTERY

DISEASE (CAD) AND PULMONARY DISEASE

AFTER ADJUVANT OR CURATIVE TREATMENT

Haugnes HS, et al., Urol Oncol 2014. See updated CVD data from Fung C et al, J Clin Oncol 2015, 33(28):3105-3115

N=92 cases, 180 controls

Testicular cancer diagnosis: 1959-1987

N=2,629 cases

RT delivered between 1960 and 1992

Stomach cancer risk Second cancer risk

SUSPECTED LONG-TERM SIDE

EFFECTS OF RADIOTHERAPY

Hauptmann M, et al., Br J Cancer 2015;112:44–51. © 2014 & 2015 Cancer Research UK. Published by Nature. This is an open access article under the

CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).

Horwich A, et al., Br J Cancer 2014:110:256–263. © 2014 Cancer Research UK. Published by Nature. This is an open access article under the CC BY-

NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).

N=307 Pts

1980-1994T

LH

FSH

(A) Testosterone, (B) luteinizing

hormone, and (C) follicle-stimulating

hormone categories over time,

adjusted for decadal age according

to treatment groupat the following

time points: baseline (BL), Survey I

(SI), and Survey II (SII)

CHANGES IN SERUM

TESTOSTERONE, LH AND FSH ON

FOLLOW-UP AFTER CURATIVE TREATMENT

Sprauten M, et al., J Clin Oncol 32 (6), 2014: 571-578

Longitudinal Serum Testosterone, Luteinizing Hormone, and Follicle-Stimulating Hormone Levels in a Population-Based Sample of Long-Term Testicular

Cancer Survivors Reprinted with permission. © 2014. American Society of Clinical Oncology. All rights reserved.

N=169 cisplatin-treated survivors of GCT

Treatment administered between January

1980 and December 1994

Cancer Registry of Norway and regional

university hospitals

(SCIN) Scale for Chemotherapy-Induced Neuropathy

NEURO- AND OTOTOXICITY IN

CISPLATIN-TREATED GCT SURVIVORS

Impact of residual serum cisplatin level

Sprauten M, et al., Impact of Long-Term Serum Platinum Concentrations on Neuro- and Ototoxicity in Cisplatin-Treated Survivors of Testicular Cancer. J

Clin Oncol 30(3);2012:3007. Reprinted with permission. © 2012. American Society of Clinical Oncology. All rights reserved.

Frisina RD, et al., J Clin Oncol 34 (23); 2016: 2712-2720

N=488 North American male GCT survivors

American-Speech-Language-Hearing Association

criteria defined hearing loss severity

HEARING LOSS AND TINNITUS

AFTER CISPLATIN-BASED CHEMOTHERAPY

Comprehensive Audiometric Analysis of Hearing Impairment and Tinnitus After Cisplatin-Based Chemotherapy in Survivors of Adult-Onset Cancer.

Reprinted with permission. © 2016. American Society of Clinical Oncology. All rights reserved.

Huddart R, et al., Br J Cancer 2005;93(2):200-7

Huyghe E, et al., Cancer 2004; 100(4):732-737

Figure from: Brydoy M, et al., Paternity following treatment for testicular cancer.J Natl Cancer Inst 2005;97:1580–8. Published under an Open Access

model by Oxford University Press

Post-treatment conception rates

vary between 59% and 82%

Preservation of anterograde

ejaculation after RPLND important

Increasing cumulative

chemotherapy doses associated

with decreased paternity rates

FERTILITY AFTER TREATMENT FOR

TESTICULAR GERM CELL TUMOURS

Details do matter in

orienting the therapeutic

choice for CSI GCT

DILEMMAS IN ACTIVE

SURVEILLANCE PROTOCOLS FOR CSI

TESTICULAR GERM CELL TUMOURS

Hanna NM & Einhorn LH, J Clin Oncol 2014, 32(28): 3085-3092. Reprinted with permission. © (2014) American Society of Clinical Oncology. All rights reserved.

RESULTS

No significant differences in outcomes

0.8% (2 scans) vs. 0.6% (5 scans) relapsed

with intermediate/poor risk GCT

Mean node diameter 2.07 vs. 2.15 cm

100% survival

N=414 randomised to 2 vs. 5 CT scans

In the 2 scan schedule, they were at 3

and 12 months

In the 5 scan schedule, they were at

3, 6, 9, 12, and 24 months

HOW SHOULD WE DO

SURVEILLANCE IN CSI? NON-SEMINOMA

Rustin GJ, et al., J Clin Oncol 2007; 25(11): 1310-1315. Reprinted with permission. ©2007 American Society of Clinical Oncology. All rights reserved

14 Abdominal CT

7 Abdominal CT

HARMONISING THE FOLLOW-UP

SCHEDULE IN CSI GCT UNDERGOING ACTIVE

SURVEILLANCE IS A MAJOR CONCERN-1

Kollmannsberger C, et al., Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: diminishing treatment-

related morbidity while maintaining efficacy. Ann Oncol 2010;21(6):1296–1301. Copyright © 2010 by permission of Oxford University Press on behalf of

the European Society for Medical Oncology

S

NS

http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site

Kollmannsberger C, et al., J Clin Oncol 2015

Vaughn DJ, J Clin Oncol 2014; 33(1): 9-12. Reprinted with permission. ©2014 American Society of Clinical Oncology. All rights reserved

HARMONISING THE FOLLOW-UP

SCHEDULE IN CSI GCT UNDERGOING ACTIVE

SURVEILLANCE IS A MAJOR CONCERN-2

RECOMMENDED MINIMUM FOLLOW-UP SCHEDULE IN A

SURVEILLANCE POLICY: STAGE I SEMINOMA

RECOMMENDED MINIMUM FOLLOW-UP

SCHEDULE IN A SURVEILLANCE POLICY: STAGE I

NONSEMINOMA

EAU Guidelines on Testicular Cancer: 2015 Update

Albers P, et al., EAU Guidelines on Testicular Cancer: 2015 Update. Eur Urol 2015;68:1054–68

Procedure Year

1 2 3 4-5

Physical examination 4 times 4 times 4 times Once/year

Tumour markers 4 times 4 times 4 times Once/year

Plain radiography chest Twice Twice

Abdominopelvic CT Twice

(at 3 and 12 months)

Once in year 2

(at 24 months)

Once in year 3

(at 36 months)

Procedure Year

1 2 3-5

Physical examination 3 times 3 times Once/year

Tumour markers 3 times 3 times Once/year

Plain radiography chest Twice Twice

Abdominopelvic CT Twice Twice At 36 and 60 months

6

12

18

24

36

48

60

DESIGN OF THE MRC-TRISST

TRIAL (NCT00589537)

Cafferty FH, et al., Clinical Oncology 2012; 24(1):25-29

Stage I testicular seminoma

(histologically confirmed)

CT scan of chest, retroperitoneum & pelvis (≤8 weeks prior to randomisation),

chest x-ray, tumour markers (AFP, β-HCG, LDH; ≤4 weeks prior to randomisation)

Randomise

165 patients

7 CTs(retroperitoneum only)

Imaging

schedule:

Month of scan:

(after

randomisation)

6

12

18

24

36

48

60

165 patients

7 MRIs(retroperitoneum only)

6

-

18

-

36

-

-

165 patients

3 CTs(retroperitoneum only)

6

-

18

-

36

-

-

165 patients

3 MRIs(retroperitoneum only)

Treatment options for CSI testicular germ cell tumours are patient-driven

Informed consent on each therapeutic strategy cannot leave out patients’ expectancies

Do not forget that treatment options, whether they are risk-adapted or not, are equal for

clinicians, not for patients

CSI patients have a good probability to be cured just after orchiecotmy, BUT surveillance

does not only mean ‘not to treat’

“Patient empowerment” can make a difference in CSI testicular germ cell tumours

‘PATIENT EMPOWERMENT’

DILEMMAS IN CLINICAL STAGE II (IIA/B) TESTICULAR GERM CELL TUMOURS

Non-seminoma: the dilemma in clinical Stage II

(Clinical Stage IIC (adenopathy >5 cm) should follow the therapeutic

algorithm of metastatic disease)

The appropriate primary intervention for CS IIA (adenopathy 2 cm) or IIB

(adenopathy 2 to 5 cm) remains controversial

Retrospective series of patients with CS II NSGCT treated primarily by

chemotherapy or retroperitoneal lymph node dissection (RPLND) have reported

survival rates greater than 95%

The decision to treat patients with CS II NSGCT initially with either RPLND or

cisplatin-based chemotherapy depends primarily on the following issues:

Extent of disease

Burden of retroperitoneal disease (single vs. multiple enlarged lymph-nodes)

Greatest node diameter (MSKCC 3 cm cut-off)

STM status post-orchiectomy

CLINICAL STAGE II TESTICULAR

GERM CELL TUMOUR – NONSEMINOMA

Not all small volume CT changes do represent disease

10-40% of patients are pathological stage I (uninvolved lymph-nodes)

Differentiation between inflammatory LN and metastatic LN is difficult

Benefit from PET for detection of occult metastases is modest

Small volume radiographic changes (<2 cm) should be confirmed by

follow-up CT in 2-4 months before starting therapy



Stephenson AJ, et al., J Clin Oncol 2007;25(35):5597-5602

Sheinfeld J, et al., J Urol 2003;170(4):1159-62

Weissbach L, et al., Eur Urol 2000, 37(5):582-94

Courtesy of the Fondazione IRCCS Istituto Nazionale dei Tumori

Debono DJ, et al., J Clin Oncol 1997;15(4):1455-64

Giannatempo P, et al., J Urol 2016;196(1):95-100

Sheinfeld J, et al., J Urol 2003;70 (4):1159-62

Issues to be considered:

Rate of teratoma in the primary

tumour (up to 82% of teratoma in

residual mass after

chemotherapy)

Teratoma (22% in CSIIA),

malignant GCT, and malignant

non-GCT in RPLND (35.7%

incidence of nodal TMT in CSI

with TMT)

Relapse rate after RPLND only

Role of adjuvant chemotherapy

after primary RPLND

Morbidity



Courtesy of the Fondazione IRCCS Istituto Nazionale dei Tumori

The presence of elevated pre-RPLND STM was associated with a 5.6-fold increased

risk of systemic relapse and was the most significant predictor of relapse after

primary RPLND



Stephenson AJ, et al., J Clin Oncol 2005; 23(12): 2781-2788. Reprinted with permission. ©2005 American Society of Clinical Oncology. All rights reserved

Rabbani F, et al., J Clin Oncol 2001;19(7):2020-2025

CLINICAL STAGE II NONSEMINOMA

The case of Adjuvant chemotherapy

The role of adjuvant chemotherapy after RPLND in patients with PN1-2 disease is

somewhat controversial

The randomised Testicular Cancer Intergroup Study showed that in patients with PS II

NSGCT, 2 cycles of adjuvant chemotherapy significantly reduced the risk of relapse

after RPLND compared to observation (6% vs. 49%), although there was no overall

survival difference

(1/3 of patients had +ve STM after orchiectomy)

Williams SD, et al.,N Engl J Med 1987;316:1435-1440

N=87

100% alive

99% relapse-free at a median FUP of 8 years

CLINICAL STAGE II NONSEMINOMA

The case of Adjuvant chemotherapy

Relapse-free and overall survival in patients with pathologic stage

II nonseminomatous germ cell cancer treated with etoposide and

cisplatin adjuvant chemotherapy

Kondagunta GV, et al., J Clin Oncol 2004; 22(3): 464-7

CLINICAL STAGE II NONSEMINOMA:

RPLND OR PRIMARY CHEMOTHERAPY IN

CSIIA,B NSGCT

Weissbach L, et al., Eur Urol 2000; 37(5):582-94

Pathological stage after primary RPLND

n PEB (randomised), n CEB (randomised), n

PS I 138 (4) actually, no chemotherapy

was given5 (5)

PS IIA/B 76 46 (30) 30 (30)

PS IIC/III 20 17 (4) 3 (3)

Overall 109 71 (38) 38 (38)

Treatment – Arm A: Primary RPLND (N=109)

Therapy Overall, n Randomised, n Not randomised, n

3 cycles PEBa 34 25 10

4 cycles PEBa (because of PR or persisting tumour markers)

15 7 7

CEBb 29 29 -

Overall 78 61 17

a15 RPLNDs after PEB b11 RPLNDs after CEB.

Treatment – Arm B: Primary chemotherapy (N=78)

Chronic toxicity in arm A (PEB or CEB adjuvant) and arm B

or (PEB or CEB inductive) in clinical stage IIA/B

Toxicity Arm A % Arm B %P value

(2-tailed)

Lung toxicity (n=88) 3.4 (n=59) 6.8 0.439

Ototoxicity (n=84) 4.8 (n=56) 5.4 1.000

Raynaud symptoms (n=100) 8.0 (n=69) 11.6 0.438

Polyneuropathy (n=92) 5.4 (n=64) 10.9 0.233

Loss of ejaculation (n=95) 31.6 (n=64) 15.6 0.012

Chronic toxicity in arm A (PEB adjuvant) and arm B (PEB

inductive) in clinical stage IIA/B

Toxicity Arm A % Arm B %P value

(2-tailed)

Lung toxicity (n=50) 4.0 (n=35) 8.6 0.399

Ototoxicity (n=50) 4.0 (n=33) 0 0.515

Raynaud symptoms (n=58) 8.6 (n=41) 17.1 0.227

Polyneuropathy (n=53) 5.7 (n=38) 2.6 0.638

Loss of ejaculation (n=56) 35.7 (n=37) 5.4 <0.001

24

0.8

0.3

0.6

36Time since end of therapy (months)

Rel

apse

–fr

ee s

urvi

val

48 60

1.0

0 72

0.4

0.5

0.7

0.9

12

Logrank-test: p=0.61

Primary chemo, n=73

Primary RPLND, n=103

Patients at risk:

103 90 73 49 31 8 0

73 59 46 33 12 5 0

Primary chemotherapy with resection of residual disease

has been accepted as standard of care for Clinical Stage II

(exception CSIIA)

RPLND + PEBx2

PROS:

• Histological confirmation of

stage (25% PSI)

• Risk of relapse low (4%)

• Simplified follow up

CONS:

• Operative morbidity for all

patients

• Chemotherapy for all patients

RPLND without CT

PROS:

• Histological confirmation

• No chemotherapy for PSI,

PSIIA/B without progress

CONS:

• 25% relapse for PSIIA

• Up to 50% relapses in CSIIB

• Close follow-up

CT + RPLND (PEBx3-4)

PROS:

• No op-morbidity for 75% of

patients with CR

CONS:

• Overtreatment for 25% of

patients

• Higher chemo toxicity

• Risk of relapse 10-15%

• Growing teratoma issue/TMT

Cure rate is 98% independent from the therapy option – minimising toxicity while

maintaining efficacy is the driver of treatment decisions

SUMMARY: TREATMENT STRATEGY

IN CS IIA/B NON-SEMINOMA

1° 1° 1° 2°

CLINICAL STAGE IIA/B SEMINOMA

Albers P, et al., EAU Guidelines on Testicular Cancer: 2015 Update. Eur Urol 2015;68:1054–68

EAU Guidelines on Testicular Cancer: 2015 Update

Clinical stage II A Clinical stage II B

Radiotherapy 2 Gy x 15 to a

target dose of 30 Gy to

paraaortic and ipsilateral

iliac field

Either

Chemotherapy 3 x BEP or 4

x EP if contraindications to

bleomycin

Or

Follow-up

Residual tumour to be followed

Chemotherapy 3 x BEP or 4

x EP if contraindications to

bleomycin

Radiotherapy 2 Gy x 15 to a

target dose of 30 Gy to

paraaortic and ipsilateral

iliac field and an additional

boost to the enlarged lymph

nodes of 2 Gy x 3 to 6 Gy

Follow-up

Either Or

Giannatempo P, et al., Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma: a systematic review and meta-analysis of patient outcomes.

Ann Oncol 2015;26(4):657-68 by permission of the Oxford University Press on behalf of the European Society for Medical Oncology



SUBGROUP ANALYSES FOR

RELAPSE OUTCOME OF RADIOTHERAPY

AND CHEMOTHERAPY STUDIES

Overall: 0.11 (95%CI: 0.08-0.14) Overall: 0.08 (95%CI: 0.01-0.15)

VERY GOOD OPTIONS BUT

NOT PERFECT

Radiotherapy vs. chemotherapy studies: Relapse-rate for CSIIA + IIB



CARBOPLATIN AND

RADIOTHERAPY FOR STAGE IIA/B SEMINOMA

Reprinted from Radiother Oncol 2001; 59(1), Patterson H, et al., Combination carboplatin and radiotherapy in the management of stage II testicular

seminoma: comparison with radiotherapy treatment alone; 5-11, Copyright 2001, with permission from Elsevier

DogLeg (35 Gy) > PA strip

(30 Gy) since 2003

REPLACING CISPLATIN WITH

CARBOPLATIN

An attractive option? YES (with radiotherapy)

Huddart R, GU-ASCO 2015; Horwich A, et al., Ann Oncol 2013; Patterson H, Radiother Oncol 2001

Carboplatin dose

Radiotherapy N Median FU No. of relapse5 yr RFS (95% CI)

Patterson 2001 400 mg/m2 Dogleg plus

boost 35Gy/18f31 48 months 2

97.5% (72.9-99.4%)

Horwich 2014 AUC 7PA strip

30Gy/15f51 55 months 0

100% (97.5-100%)

Studies of carboplatin in stage I disease have suggested it can reduce the risk of

recurrence due to microscopic disease

Toxicity (number assessed) Grade No. of patients

Nausea (51) 0

1

2

3

16

10

24

1

Diarrhoea (51) 012

3894

WBC (50)a >1 12

Platelets (50)a >1 6

A multi-centre Phase II Study using carboplatin AUC-10 for metastatic seminoma

with IGCCCG good prognosis disease-therapy directed by initial metabolic

response on PET-CT (Car-PET) (NCT02272816)

Sample size: N=50

IGCCCG Good Risk Seminoma

CBDCA AUC 10 x 1 > early PET response > CBDCA AUC 10 x 2-3

Carboplatin AUC7 followed by involved node RT for stage IIA/B seminoma

(NCT01593241) (NCT01593241)

Swiss Group for Clinical Cancer Research (SAKK) - German Testicular Cancer

Study Group (GTCSG

Magnetic resonance imaging and computed tomography in patients with

Stage I seminoma of the testicle (TRISST, NCT00589537)

Relapsing disease: Data collected on CBDCA+RT

ONGOING STUDIES

Both chemotherapy and radiotherapy did provide excellent results in Stage IIA and

IIB seminoma, and sustained at long term

However, in testis cancer details of pros & cons for each therapeutic option do

matter

These details would favour the use of standard cisplatin-based chemotherapy for

CSIIB patients, while for CSIIA chemotherapy and radiotherapy are equal options

HOWEVER:

These patients exhibit a very good prognosis overall, and 3 cycles of BEP

chemotherapy are being increasingly thought to be an overtreatment

Consequently, attempts to mitigate the long-term side effects of chemotherapy and

to reduce radiotherapy field and doses are warranted

With this aim, the combination of carboplatin and involved-nodes RT is rationale in

selected patients and should be pursued

CSII A/B SEMINOMA

CONCLUDING THOUGHTS

THANK YOU!

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