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The role of adjuvant therapies and surveillance in stage I testis cancer

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The role of adjuvant therapies and surveillance in stage I testis cancer. Johnathan Joffe ... arm study of BEP as adjuvant chemotherapy in high-risk stage-1 ... – PowerPoint PPT presentation

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Title: The role of adjuvant therapies and surveillance in stage I testis cancer


1
The role of adjuvant therapies and surveillance
in stage I testis cancer
  • Johnathan Joffe
  • Macmillan Consultant in medical Oncology
  • Calderdale Huddersfield NHS Trust and Leeds
    Teaching Hospitals NHS Trust

2
Seminar on stage I testis cancer
  • Not limited to seminoma, carboplatin and
    surveillance
  • Brief (personal) overview of current management
    and International opinion
  • Discussion
  • NCRI Testis Group planned studies
  • Discussion

3
EGCCCG Consensus 2007
  • SEMINOMA Stage I
  • A surveillance strategy should be used as the
    preferred treatment option in patients in whom
    this approach is considered feasible (EBM IIB
    116,117). This recommendation takes into account
    that 80-85 of patients are cured by orchiectomy
    and are therefore overtreated by any adjuvant
    treatment.
  • NSGCT Stage I
  • Patients with a low risk of relapse (no VI)
    should be managed by surveillance according to
    the EGCCCG recommendations for follow-up ..
  • Patients with a high risk of relapse (VI
    present) should receive adjuvant chemotherapy
    with two cycles of BEP .
  • Nevertheless, if surveillance is carried out
    properly gt98 of these patients will still have a
    good prognosis and are cured by chemotherapy at
    the time of relapse

4
Stage I SeminomaNatural history
  • Historical Surveillance studies
  • Warde Retrospective Data
  • Spanish Prospective studies (Risk adapted
    strategy)
  • Salvage
  • 75 80 RFS
  • 0 factor 88 RFS
  • 1 factor 83 86 RFS
  • 2 factors 68 RFS
  • 0 factors 95.8 RFS, OS 100
  • (1st study 83.9 risk factors L1/pT2)
  • 99 Cause-specific Survival

5
Seminoma Adjuvant therapies
  • Para-aortic strip 20Gy 96 RFS
  • TE19 carboplatin AUC 7 - 96 RFS
  • Late effects
  • Cost / Service utilisation Inconvenience
  • Over-treatment 68 86
  • Salvage 99
  • Data immature
  • Convenience
  • ?Contralateral effect
  • Over-treatment 68 86
  • Salvage 99 (?)

6
Seminoma Surveillance
  • Compliance
  • Acceptability
  • Duration
  • Intensity
  • Risk
  • If doubts adjuvant therapy prefered
  • Patients may prefer Rx
  • Standard practice 10years
  • CT Intense
  • Radiation 2nd Malignancy

7
Seminoma Suggested strategies
  • Low Risk (0/1factors)
  • High risk (2 factors)
  • Uncertain ?
  • Promote surveillance
  • Offer adjuvant therapy for special cases
  • Offer a choice
  • ? Need for useful clinical study

8
NSGCT Stage INatural History
  • Historical Surveillance
  • TE05 (High Risk) post BEP (360) x 2
  • BEP 500 x1 (Vs RPLND)
  • Salvage
  • OS
  • 68-73 RFS (27-32)
  • Low risk 78-86RFS
  • High risk 42-60 RFS
  • 98
  • 98.9 (vs 92.5)
  • gt90
  • 99

9
NSGCT Adjuvant therapy
  • BEP (360) x2
  • high risk
  • Low risk
  • Cost
  • Risks - short / long-term
  • Neutropenia
  • Fertility
  • Over-treatment gt50
  • 33 more cycles than Rx relapse on Surveillance
  • Over-treatment lt80
  • gt300 more cycles than Rx of relapse

10
NSGCT Surveillance
  • Compliance
  • Acceptability
  • Duration
  • Intensity
  • Risk
  • If doubts adjuvant therapy prefered
  • Patients may prefer Rx
  • Standard practice 5years
  • CT Less intense following TE08
  • Radiation exposure less since TE08

11
NSGCTSuggested strategies
  • Low Risk
  • High Risk
  • Uncertain ?
  • Promote surveillance
  • Offer adjuvant therapy for special cases
  • Promote Surveillance
  • Offer a choice
  • ? Need for studies

12
Discussion
13
NCRI Testis Working Group Studies considered
  • SEMINOMA
  • Carbo x 2
  • Surveillance studies
  • TE24 - TRISST
  • NON-SEMINOMA
  • German 1vs 2 -BEP (500) study (poor recruitment)
  • Surveillance study (PASST)
  • 111 BEP Study
  • (PPP Study)

14
Rationale for TE24 TRISSTTRIAL OF IMAGING AND
SCHEDULE IN SEMINOMA TESTIS
  • Risk of 2nd malignancy following 7CTs 1300 (100
    200mSv)
  • Occupational exposure estimates for gt100mSv is
    9.7 risk of non-leukaemia malignant death 19
    risk Leukaemia death.
  • Reduction in Radiation exposure is worthwhile and
    can be achieved by reduced CT or switch to MRI

15
TE24
  • Patient inclusion criteria
  • 1.Histologically proven seminoma of the testis
    without evidence of NSGCT elements.
  • 2. Clinical stage I on the basis of clinical
    examination and CT scan of the chest, abdomen and
    pelvis.
  • 3. No planned adjuvant therapy.
  • 4. Normal serum AFP pre-orchidectomy and at
    randomisation.
  • 5. Normal serum ß-HCG at randomisation (may have
    been raised pre-orchidectomy).
  • 6. Patient written, informed consent.
  • 7.Patients must be able to attend for regular
    surveillance.
  • 8. The interval between orchidectomy and
    randomisation lt 8 weeks.
  • 9. Patients must be at least 16.
  • Patient exclusion criteria
  • 1.Co-existent or previously treated malignancy
    within 10 years other than successfully treated
    non-melanoma skin cancer.
  • 2.Inability to comply with the trial
    investigations or follow-up schedules.
  • 3. Any contra-indication to MRI, for example,
    ferrous metal implants of any type, cardiac
    pacemaker or defibrillators, or history of injury
    by metal fragments.

16
Trial of Imaging and Schedule in Seminoma Testis
TRISST TE24
17
TE24 (TRISST)
  • TRISST is a non-inferiority, factorial,
    randomised trial.
  • The aim is to show that both the new and standard
    interventions have similar levels of
    effectiveness or adverse events.
  • Primary outcome
  • Proportion of patients relapsing with Royal
    Marsden Hospital (RMH) stage IIC (frequency and
    modality)
  • Secondary outcomes
  • 1.      Mean abdominal mass size at relapse (CT
    vs MRI)
  • 2.      Time on surveillance before relapse
  • 3.      First modality to detect relapse
  • 4.      Extent of relapse according to IGCCCG
    1997
  • 5.      Disease free and overall survival
    according to schedule randomisation and
    prognostic grouping
  • 6.      Prospective evaluation of prognostic
    factors for relapse
  • Health economic assessment

18
TRISST Sample Size The estimated 5-year relapse
rate for these patients is 15, based on the
assumption that the population will comprise
mainly those with one or no risk factors, as
identified by Warde et al 3.  Sample size
calculations are based on the characteristics of
patients relapsing on carboplatin in the MRC TE19
trial 16 and from the surveillance studies
17. In both settings, 89 of patients who
relapsed had para-aortic node involvement. In
TE19, the mean size of retroperitoneal nodal
relapse after carboplatin was 4cm (SD 2cm), and
38 of relapses were of RMH stage IIC or
greater. All patients contribute to both
comparisons (CT vs MRI and more vs less frequent
imaging). To exclude an increase in the
proportion of relapses with RMH Stage ?IIC from
38 to 76 through either a move from CT to MRI,
or from more frequent to less frequent scanning,
would equate to excluding a change in the
proportion of all randomised patients relapsing
with higher stage disease from 5.7 to 11.4.
For this latter comparison, 630 patients provides
80 power to exclude a difference at least this
great (5 significance level, 1-sided). We
anticipate that some patients (lt5) will find MRI
unacceptable and thus have inflated the sample
size to a target recruitment of 660
patients.  This primary analysis includes all
randomised patients if stage at relapse is
compared only in those who relapse - assuming 15
of patients relapse, 95 relapses would be
observed - the power to exclude an increase from
38 to 76 in the proportion of relapses at stage
IIC or greater would be over 95 (5 significance
level, 1-sided).  For the scan modality
comparison in particular (CT versus MRI), the
size of abdominal mass at detection of relapse is
an important additional outcome measure. The
confirmatory CT scan that is carried out on
patients whose relapse is detected by other
means, will ensure comparability of mass size.
Although small changes in mass size are not of
major clinical significance in testis cancer
patients, the results of this comparison may have
relevance to other cancers. 530 patients (70 PA
node relapses, 79 relapses in total) would be
required to exclude a 1cm increase in the mean
size of abdominal masses (standardised difference
0.5, power 90, 5 significance level, 1-sided).
Some caution is needed with this analysis
because, although it would include all relapsed
and followed patients regardless of first mode of
detection of relapse, it cannot include all
randomised patients, introducing the potential
for bias. However as the trial interventions
affect only the timing of relapse, and not
whether or not it occurs, any bias would be
minimised by ensuring adequate follow-up in both
groups beyond the time of the final
scan. Patients will be asked to consent to be
randomised to any of the four surveillance
methods. If this impacts adversely on recruitment
for example if centres or patients have a strong
preference for CT-based surveillance, or
inadequate access to MRI, then consideration in
the future may be given to allowing randomisation
either between the two scanning schedules (using
CT in all patients), or between CT and MRI (with
the same scan frequency in all patients). This
would however substantially increase the overall
sample size.
19
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20
Rationale for 111 BEPSingle-arm study of BEP
as adjuvant chemotherapy in high-risk stage-1
non-seminomatous GCTs
  • BEP 500x1 Vs RPLND unlikely to influence
    practice
  • German BEP500 1 vs 2 slow recruitement and the
    wrong study for UK practice
  • 3 small studies of BEP500 x1 suggesting very low
    relapse rates
  • Randomised UK study BEP500 x1 vs BEP360 x 2
    unlikely to recruite adequate numbers
  • Randomised BEP vs surveillance un-popular and
    numbers large
  • Single arm study with adequate statistical power
    could influence practice, particularly if safe

21
Rationale for 111 BEPSingle-arm study of BEP
as adjuvant chemotherapy in high-risk stage-1
non-seminomatous GCTs
  • UK SURVEY
  • Of 28 respondents, 8 stated that they treated all
    high risk stage 1 patients with 2 cycles of BEP
    5 put all such patients onto a surveillance
    program and 15 used both treatment strategies
    with the proportion of patients receiving 2
    cycles of BEP ranging from 5 to 95
    (median80).
  • If the proposed trial confirms that the relapse
    rate following BEP1 is no worse than 5 compared
    to 2 with BEP2 the Protocol Development Group
    believe that the UK clinical community could be
    convinced to switch from BEP2 to BEP1 and that
    further standardisation of treatment could be
    achieved through a proportion of patients
    currently offered surveillance being prepared to
    consider a single cycle of chemotherapy. The
    results of this study will therefore inform
    clinical decision making and could change
    management practice globally.
  • 26/27 respondents indicated that they would enter
    patients into a single arm study of 1 cycle of
    BEP and 22/27 indicated they would enter patients
    into a randomised study of 1 cycle of BEP vs.
    surveillance with a long-term toxicity endpoint.

22
111 BEP
  • Inclusion Criteria
  • men aged 16 years
  • newly diagnosed NSGCTT or mixed GCT (MGCT) with
    vascular invasion and stage1 disease
  • normal tumour markers and CT scan
  • within 6 weeks of orchidectomy
  • written informed consent
  • Outcome measures
  • Primary Recurrence
  • Secondary Immediate and delayed toxicity
    including permanent infertility

23
111 BEP Sample size
24
Safety Rationale for PPP Study
  • 111 BEP needs to be safe Rx
  • Main short-term risk is Neutropenic infection
  • Significant study suggests benefit for
    prophylactic antibiotics routine in some
    departments
  • Safety issues apply to BEP in all settings where
    greatest risk may be in the first cycle.

25
PPPA phase III randomised trial of primary,
prophylactic pegfilgrastim following one cycle of
BEP chemotherapy in non-seminomatous germ cell
tumours of the testis
  • Inclusion Criteria
  • Men aged gt15
  • Newly diagnosed NSGCT (any stage)
  • About to commence at least one cycle of BEP
  • Written informed consent
  • Outcome Measures
  • Primary Febrile episodes
  • Secondary Number of severe infections
    hospitalisations for investigation or Rx of
    Infection

26
PPP Sample Size
  • The trial will recruit 326 patients. This is
    based on detecting a 75 reduction in FE
    (absolute difference 7.5) between the control
    and PPP treatment groups. In the control group,
    10 of patients are expected to have a
    FE (Significant trial subset -accepted JCO). It
    is anticipated that an FE rate 2.5 or less in
    the PPP group would warrant cost-effective
    adoption of the use of proylatic pegylated G-CSF.
    Personal experience of the combination (MHC)
    suggests this might be realistic. Using a two
    group Chi-squared test of equal proportions (not
    continuity corrected), power80, 2-sided
    alpha5, 163 patients per group are required.

27
Discussion
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