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F_Nicola Nicolai_Controversies in treatment and surveillance of clinical stage I seminoma and nonseminoma testis cancer

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					Mediterranean School of Oncology
Highlights in the Management of
Urogenital Cancer
Rome, May 9-10, 2008

Controversies in treatment and surveillance of
clinical stage I seminoma and nonseminoma testis
cancer
Nicola Nicolai, Milan




                     Sc Urologia

         Italian Germ-cell cancer Study Group
             Background

• Germ-cell tumors (GCTs) are rare, 1%
  only of solid tumors
• Age of onset (20-40 yrs old) is critical
• Highly curable neoplasms: almost 90% of
  patients are cured
          Low-stage GCTs

• There is no Consensus concerning low-
  stages (stage and therapy)
• In contrast with what we have reached in
  advanced disease (IGCCCG, 1997)
        Low-stage GCTs (2)
• Prognosis is not the main issue of low-
  stage disease
• In fact, the global outcome is
  extraordinarily favorable as nearly 98-99%
  of low-stages patients are cured
• QoL is the main issue
• QoL depends on: early and late toxicity of
  treatment and critical age of patients
Non-seminoma stage I

   Staging and Therapy
     Clinical stage I NS: common
               landmarks
• Definition  No evidence of disease beyond the
  testis (normal t/2 markers decay following
  orchiectomy, normal imaging, as recent as
  possible)
• Cure-rate: 98-99%
• 50 - 70% of NS are diagnosed at this stage:
  treatment at this stage is crucial for the best
  global outcome (cure & morbidity) in most
  patients
• Risk factors: vascular invasion (VI), %ECa,
  others
    Medical Research Council
     Model (the only validated
           predictive model)
• Risk factors: venous invasion, lymphatic
  invasion, no YST, presence of ECa
• ≥ 3 factors  high risk: 20% of patients,
      50% of them bearing occult metastases
• < 3 factors low risk: 80% of patients, 20%
  of them bearing occult metastases
 European Consensus Conference on Diagnosis and Treatment of
     Germ Cell Cancer: A Report of the Second Metting of the
    European Germ Cell Cancer Consensus Group (EGCCCG).
                     Eur Urol 2008;53:497

• Algorithm after orchiectomy for stage I NS
• Low-risk (no VI)  standard: surveillance
                      alternative: 2 PEB
                                    RPLND

• High-risk (VI)           standard: 2 PEB
                           alternative: surveillance
                                         RPLND
2587 pts
VI OR 5.2
Availability of Vascular
 Invasion information
 (Nicolai et Al, J Urol 2004)

  No. VI (%)
   Absent          131 (41)
   Present         72 (22)
   Not available   119 (37)
 Reliability of VI information: Local (L) Vs
Central Pathology (P) (Sesterhenn et Al, J Clin
                   Oncol, 1992)
             Central pathology review
             Absent       Present        Total
 LP diagn.
 Absent      201          135     ~40%   336
 Present     16    ~30%   38             54
 Unknown     18           6              24
 Total       235          179            414
Reliability of VI information: Local (L) Vs
Central Pathology (P) Fondazione INT, AUA
                  Proc 2008)
            Central pathology review
            Absent      Present        Total
LP diagn.
Absent      24          7      ~23%    31
Present     5    ~15%   28             33
Unknown     55          19             74      ~56%

Total       84          54             138
   Vascular Invasion (as it is!)
• Many reports (nearly 50%) do not contain
  this information
• There is a discrepancy of about 20%
  between first diagnosis and central review
• If this information is not reported and
  possibly reviewed, up to 70% of patients
  are randomly or wrongly treated in
  respect of the main prognostic factor!
    Decision Making by issues
• Ease of use of therapy (single shot
  therapy)
• Complexity of administration
• Simplification of follow-up
• Late relapses
• Early and late toxicities
    Decision Making by issues
• Ease of use of therapy (single shot
  therapy)
• Complexity of administration
• Simplification of follow-up
• Late relapses
• Early and late toxicities
Ease of use of therapy
Active surveillance   Orchiectomy “only”
                      Intensified Observation: 30%
                      chemotherapy and also surgery in 15-
                      20% of cases.


RPLND                 4 wks of loss of time (hospital stay
                      and convalescence)
                      Further therapy in case of relapse in
                      10-15% of cases

Chemotherapy          5 wks of loss time (administration
                      and recovery)
                      Further therapy in 2-3% of cases
     Adj ChT ≥ RPLND ≥ surv?
DISTRIBUTION OF NODAL METASTASIS IN NSGTC
                                    J.P.Donohue J.Urol., 1982



                         0%                                                          14%
                                    0%                                    7%




                                                                      29%
                     88%
         12%                        4%                      0%                       79%
                                                                 0%            71%
               40%            23%


                                                                                           14%
    8%

                                                                      14%
          4%        4%                                          0%
               0%                                                    0%




     Right tumor                                          Left tumor
Sympathetic retroperitoneal chain
Full bilateral (infra-hilar) nerve sparing RPLND
Modified bilateral RPLND for right tumor
Modified bilateral RPLND for left tumor
  Post-chemotherapy (PC) RPLND
          and ejaculation

• Coogan et Al (Indiana Univ) J Urol, 156:
  1656, 1996
• preservation of normal ejaculation in
  76.5% of 81 patients undergoing nerve
  sparing PC RPLND
Complexity            Adj ChT > Surv > > RPLND?
Active          High compliance, (due to experience and
surveillance    ability of clinicians in administering proper
                information and confidence)
                Does not avoid retroperitoneal surgery  high
                surgical experience in order to keep antegrade
                ejaculation in patients submitted to post-Cht
                RPLND
RPLND           High specialisation
                Best results achieved in high volume centres
Chemioterapia   Proper knowledge is requested to plan an
                adjuvant treatment
                A sophisticated competence to administer 2
                courses of PEB is not needed (!)
    Decision Making by issues
• Ease of use of therapy (single shot
  therapy)
• Complexity of administration
• Simplification of follow-up
• Late relapses
• Early and late toxicities
            Follow-up: NS
• No consensus exists
• Schedules tend to be less intensive in
  case of active treatment
• Follow-up schedule is the treatment when
  active surveillance is chosen
• Different schedules may give different
  results
Sites of relapses following active
           surveillance
(from Stephenson & Sheinfeld Curr Treat
         Options Oncol, 2005)
Results of surveillance studies (Segal Uro Oncol:
       Seminars and Original Invest 2006 68–74)
       Active surveillance Vs RPLND: INT experience

Treatment        Surveillance 1981-84: RPLND 1985-95:
                         85 pts             322 pts
Tot N/M +       25 (29,4%)             89 (27,6%)
N+/pN+ only     11 (12,9%)             40 (12,4%)
N+/pN+ & M+     3 (3,5%)                       20 (6,2%)
M+ only         11 (12,9%)             43 (13,4%)
Late relapses   4/85 (4,7%)            3/322 (0,9%)
                4/25 (16%)             3/49 (6,1%)
DSS             96,5%                  98,8%
DOD/DWD         3 (2 RP)               4 (all lung mets)
     RPLND: therapeutic role




31/44 pN+  M0: 70.5%   Nicolai et Al, J Urol, 2004
            Adjuvant Chemo in CS I NS
   (from Stephenson & Sheinfeld Curr Treat Options Oncol,
                          2005)
Study         #pts   Median f-   Relapse     RP      DOD (%)   DDT (%)
                      u, mo        (%)     relapse
                                             (%)
Oliver et     148       33        6 (4)     NR       2 (1.4)
Al, 2004
Cullen et     114       48       2 (1.7)   2 (100)     0        1 (.8)
Al, 1996
Amato et      68        38       1 (1.5)   1 (100)     0
Al, 2004
Bohlen et     59        93        2 (3)    2 (100)   2 (1.5)
Al, 1999
Pont et Al,   29        79        2 (7)    2 (100)   1 (3.5)
1996
Teratoma in RP lymph-nodes following
primary RPLND (from Carver & Sheinfeld Nat
          Clin Practice Urol, 2005)
    One Course of adjuvant PEB Vs RPLND in
    patients with stage I NSGCTT: results of the
       German Prospective Multicentric Trial
              (Albers et Al, ASCO proc 2006)
•   1996-2005: 382 pts  ® 1 PEB Vs RPLND
•   PS II at RPLND  2 PEB
•   346 valuable: 172 RPLND, 174 PEB
•   Median F-U: 47 mos (93% with 1 yr of minimum f-u)
•   13 (8%) relapses among RPLNDs* (3 in RP, 3
    markers elevation, 2 inguino-scrotal relapses)
•   2 (1%) relapses among PEBs (1 MT in RP, 1
    markers elevation)
* 15 recurrences in updated series presented at 2008 EAU
    conference (Milan, March 2008)
               Late Relapses (LR)
         (Geldart et Al, Brit J Urol 98, 2006)

•   1980-2004: 742 NSGCT of the testis
•   405 Metastatic disease
•   329 CRs (101 or 31% needed surgery too)
•   18 early relapses
•   20 LR, median time 108 (26–217) mos (≈ 9 years)
•   15 surgery alone        14 NED at 44 (9-184) mos
•   5 chemotherapy          1 NED
Follow-up        Ad ChT = RPLND >> surv?
Active         30% of relapses
surveillance   Following 2° yr yet (16% of relapses in INT
               series)

               8-14% of relapses (with and with no
RPLND          adjuvant chemotherapy)
               < 1% following 2° yr ( less intensive
               follow-up)
               Abdominal relapses rare (1-2%) (less TC!)



               2-3% of relapses
Chemotherapy
               Late relapses are possible and not yet
               explored
Late relapses       RPLND >> Adj ChT > Surv?

 Active         Late relapses have been reported, usually
 surveillance   abdominal and large masses.



 RPLND          <1% in different series.
                Surgery is the key-therapy for these relapses
                (early surgery means prevention)

                2-3% relapse-rate.
 Chemotherapy
                Almost all are retroperitoneal: from half to all of
                these pts will not be cured.
                Chemoresistant o chemo-insensitive disease
                (teratoma) in retroperitoneum.
                Follow-up period not enough to valuate the
                occurrence of late relapses.
    Decision Making by issues
• Ease of use of therapy (single shot
  therapy)
• Complexity of administration
• Simplification of follow-up
• Late relapses
• Early and late toxicities
               primary RPLND morbidity
                          I.N.T.          Indiana       German
                         Milano1        University2   Study Group3
Loss of AE              1% if unilat     2% if NS         6,7%
                        < 4% if bil
Re-                        <1%             <1%            <1%
intervention
Mortality                     0           0,2%             0
Abdominal                   1,8%          1,1%           1,3%
recurrences             infield 0,3%?    infield 0%    infield 0,8%
1 unpublished
2 Donohue et Al J Urol, 1993
3 Heidenreich et Al J Urol, 2003
  CardioVascular Events (CVE)


• Huddart et Al, J Clin Oncol 2003
• 68/992 (6.9%) CVE among pts treated for
  GCTC (1982-92) after a median follow-up
  of 10.2 yrs
Cardiovascular events
(Huddart et Al, JCO, 2003)
              Second cancers
•   Travis et Al, J Nat Cancer Inst 97:1354, 2005
•   14 tumor registries northam/eur 1943-01
•   40576 pts with testis ca &1 yr of min survival
•   2285 second solid cancers
•   RR 2.0 following RT
•   RR 1.8 following ChT
•   RR 2.9 following both RT & ChT
•   RR tends to decrease for non-seminomas
    which were treated since1975
                    Second cancers




Travis et Al, J Nat Cancer Inst 97:1354, 2005
Toxicity          RPLND > Surv ≥ Adj ChT?
 Active         Intensive observation  anxiety.
 surveillance   Full dose chemotherapy for relapsed pts  risk
                of cardiovascular disease and 2° cancer.
                Greater risk of loss of AE among pts who
                relapsed and submitted to post-ChT RPLND (2/3)


 RPLND          Avoids chemotherapy in 90% of pN0 patients
                and in 70% of pN+ patients.
                Loss of antegrade ejaculation  < 2% in “high
                volume” centres



 Chemotherapy   Toxicity may be severe also following just 1-2
                cycles of ChT.
                Hypothetical risk of cardiovascular disease (2°
                cancer?).
   Decision analysis by issues
                           Clinician-oriented Decision

• Ease of use of         • Cht ≥ RPLND ≥ Surv
  therapy (single shot
  therapy)
• Complexity of          • Cht > Surv >> RPLND
  administration
• Simplification of
  follow-up              • Cht = RPLND >> Surv
• Late relapses          • RPLND >> Cht > Surv
• Early and late         • RPLND >> Surv ≥ Cht
  toxicities
                            Patient-oriented Decision
Laparoscopic retroperitoneal
  lymph-node dissection
         Lap-RPLND
   Lap-RPLND in testis cancer
• Possible applications
  – As staging and therapeutic procedure (primary or
    post-ChT)
• Advantages
  – Less invasive than open RPLND
• Criticisms
  – Is it curative? In case of nodal metastasis at staging,
    adjuvant chemo is required (more chemotherapy)
  – Is it cost-effective?
Risk adpted RPLND
   (open Vs Lap)
 Risk factors for pN+ (Nicolai et Al, J Urol 2004)

• # pts: 322
• Considered factors:        V+
                             %ECa > 90%
• Risk assignement:     high  ≥ 1 factor
                        low  no factor

• Risk Categories :
           “low-risk” for pN+ (<14%)
           “high risk” for pN+ (35%)
 “Oncologic efficacy of laparoscopic RPLND in
 treatment of clinical stage I nonseminomatous
 germ cell testicular cancer.” Nielsen ME et Al Urology 2007.
Clinical stage I   No 120   Post-RPLND        Relapses Site of relapse
                            Rx
Pathologic         74 (62%) 74 surveillance    7 (9%)   4 chest
stage I                                                 2 pelvic1
                                                        1 biochemical
Pathologic         46 (38%) 36 (78%)  2-3       0
stage II                    PEB (3-4 wks
                            within)
                            10 (22%)         2 (20%)   1 chest
                            surveillance                1 biochemical

  Template unilateral dissection behind lumbar vessels
  1outside surgical boundaries
“Quality of life after lap and open RPLND in clinical
stage I nonseminomatous germ cell tumor: a
comparison study”. Poulakis V et Al, Urology 2006;68:154.
test                   Lap-RPLND                    Open-RPLND          Statistical
                          # 21                         # 29            significance
Visual            Baseline 0.8 (±0.3)                 1.1 (± 0.4)          NS
analogue pain     1 mo     3.0 (±4.9)                 5.2 (±4.6)          < .001
score             6 mos    1.1 (±2.0)                 3.2 (±3.2)
Overall           Baseline 0.9 (±0.8)                 1.0 (±0.7)           NS
disturbance by    1 mo     3.4 (±4.5)                 5.3 (±4.1)          < .001
pain              6 mos    1.2 (±2.1)                 3.4 (±2.9)
SF-36            Physical functioning, social       Significantly better in 6/6
                 functioning, roles physical
                 restrictions, bodily pain,
                                                    domains
Questionnaire
                 general health, vitality

EORTC QLC-       Physical functioning, role         Significantly better in 7/7
                 functioning, emotional
C30              functioning, social functioning,
                                                    domains
questionnaire    global QoL, fatigue, pain
                     Lap-RPLND
•   Albqami & Janetschek, J Endourol 19 (6):683, 2005
•   2001-4: 103 CS-I pts (further 59 with CS II disease)
•   median fu: 62 mos (6-113)
•   Technique: lap-dissection of tissue ventral to lumbars
    vessels plan
•   3 conversions (2.9%) to open procedure
•   4 minor complications
•   Median ot 217 min; blood loss 144 ml, mean hospital stay
    3.6 days
•   26 pN+  adjuvant chemo  no relapse
•   77 pN0  observation  93.5% MFS & 5 relapses 1 RP, 3
    lung, 1 markers only  chemo  100% NED
•   Antegrade ejaculation preserved in 100% of 100
    evaluable patients
                  Lap-RPLND
• One surgeon INT experience
• 2002-7: 43 “low-risk” CS-I pts
• current technique: lap-dissection of tissue as in open
  procedure
• 3 conversions (7%) to open procedure (1st one)
• 3 complications controlled without conversion
• mean ot 203 min; median hospital stay 4 days
• 3 pN+  2 adjuvant chemo  no relapse
             1 surveilled  super-hilar relapse
• 40 pN0  observation  97.5% MFS & 1 relapse: 1 RP 
  PEB x 3  100% NED
• Antegrade ejaculation preserved in 100% of evaluable
  patients
                    Lap-RPLND

Advantages                            Disadvantages
Lower morbidity                       Technical demanding procedure
shortens (half) hospital stay         Only diagnostic (?)
reduces convalescence period          Tends to increase ChT (if
reduces social costs                  unselected pts)
mantained AE                          Cool
Staging role
Therapeutic role(?)  good evidence
Cool
Seminoma Stage I

 Staging and Therapy
 European Consensus Conference on Diagnosis and Treatment of
     Germ Cell Cancer: A Report of the Second Metting of the
    European Germ Cell Cancer Consensus Group (EGCCCG).
                     Eur Urol 2008;53:497




• Algorithm after orchiectomy for stage I S
•  standard:        surveillance
   alternative:     1 Carboplatin AUC 7
                     Radiotherapy PAS 20 Gy
    Clinical Stage I Seminoma
• About 15-20% of untreated patients will
  relapse (usually in the retroperitoneum)
• For more than half a century, RT has been
  represented the standard treatment
• Traditional adjuvant therapy (PA and iliac
  RT  Dog Leg at 25-30 Gy) reduced to
  less than 5% occurrence of relapses
       Early stage seminoma

• 75-90% of seminomas are diagnosed
  when at clinical stage I
• Definition: as for Clinical Stage I non-
  seminoma
• An elevation of AFP is not consistent with
  a diagnosis of seminoma
               Morbidity e 2° cancers
• Early Tox: GI, hematological
• Fertility (1 yr to be reversible)
• Cardiovascular: 2.3 HR for hearth death (infra- and
  super-diaphragmatic RT; but still significant also for
  infradiaphragmatic RT (T 10-11)
• Hodgkin L, RCC, bladder, and gastric ca. (not significant
  increase following infra-diaphragmatic RT)


  Hanks et Al, Int J Radiat Oncol Biol Phys, 24:913 1992
  Dieckamm et Al, Oncology, 51:450, 1994
  Ruther et Al, Oncology, 58:75, 2000
  Huddart et Al JCO, 21:1513 2003
  Zagars et Al, JCO, 22:640 2004
  Travis et Al, J Nat Cancer Inst 97:1354, 2005
 Second Cancers in pts with testis neoplasm
      (S & NS) who survive > 10 yrs
        (from Duchesne G, ASCO GU meeting 2008*)
Tumor (solid)                                  RR (95% CI)
Lung                                           1.5 (1.2-1.7)
Esophagus                                      1.7 (1.0-2.6)
Colon                                          2.0 (1.7-2.5)
Bladder                                        2.7 (2.2-3.1)
Mesothelioma                                   3.4 (1.7-5.9)
Pancreas                                       3.6 (2.8-4.6)
Stomach                                        4.0 (3.2-4.8)
Connective Tissue                              4.0 (2.3-6.3)
*derived from Travis LB et Al, J Natl Cancer Inst 2005;97:1354
 Clinical practice change in the last
               10 years
• The majority (56%) of canadian
  practitioners in 2001recommended RT as
  the best option for stage I seminoma
• By 2006, the majority favors active
  surveillance
• In UK, a single cycle of Carboplatin is now
  the most frequently offered treatment
  modality

(Huddart Clin Oncol (R Coll Radiol) 2006;18:693)
   Clinical Stage I Seminoma

• Opportunity of cure for relapsed patients
  and late effects of radiation lead to new
  perspectives:
• Omission of therapy following orchiectomy
• Modification of RT administration
• Adjuvant Chemotherapy
   Results of surveillance in stage I seminoma
                (from Warde PR, ASCO GU meeting, 2008)

Series                # pts    Median # relapses         % Cancer
                              Follow-up   (%)            Specific
                                                         Survival
Germa Lluch et Al      45        34        5 (11)          100
Horwich et Al          103       62       17 (17)          100
Oliver et Al           67        61       16 (24)          97
Ramakrishnan et Al     72        44       13 (18)          100
Daugaard et Al         394       60       69 (18)          100
Warde et Al            421       98       64 (15)         99.7
        Active Surveillance

• Warde et Al (JCO, ’02), multicentric study
• 638 pts
• 19% of relapses after a median f-u of 7
  yrs
• 69% within 2 yrs
• 7% after 6 yrs
• 5yr-OS: 98%
Clinical Stage I Seminoma: risk factors
 • T size (≤ 4 Vs > 4 cm) and rete testis invasion
   are independent factors at multivariable analysis
 • 5-year relapse rate as follows:
 • both factors (only 15% of pts)          31.5%
 • only one factor                         15.9%
 • no factor                               12.2%
 • 6.6% of relapses occurring more than 6 yrs after
   orchiectomy

 Warde P et al JCO 20:4448, 2002
      Clinical Stage I Seminoma: risk
             adapted treatment
•   314 pts btw 1999 and 2003
•   100 (31.4%) no risk factors  surveillance
•   131 (41.7%) T > 4 cm               |
•   33 (10.5%) rete testis invaded     |Carbo x 2
•   50 (15.9%) both factors            |
•   7.9% G 3-4 hematological toxicity
•   F-U of 12 to 72 months
•   6 (6%) relapses among pts on surveillance
•   7 (3.3%) relapses among treated pts
•   All rescued by EP
    Aparicio J et al JCO 2005;23(43):8566
     Evolution of Rx in Clinical Stage I
          Seminoma: MRC trials
• MRC TE 10  dog leg (DL) Vs
            para-aortic strip (PAS) RT
Fossa et Al, JCO 17:1146, 1999

• MRC TE 18                   30 Gy Vs 20 Gy
  (EORTC 30942)
 Jones et Al, JCO 23:1200, 2005

• MRC TE 19                   RT (20/30 Gy) Vs single
  (EORTC 30982)                dose Carboplatin
 Oliver et Al, Lancet 366:293, 2005
     MRC TE 10: PAS Vs DL RT
• Fossa et Al, JCO 17:1146, 1999
• 1989-93: 478 pts (PAS 236, DL 242)
• median fu: 4.5 yr
• 18 relapses (9 each arm: 4 pelvic in PAS arm)
• 3yr rel-free survival:  PAS 96% (95-99%)
                          DL 96.6% (94-99%)
• 3 yr survival:          PAS 99.3% (1 DOD)
                          DL 100%
• Acute tox: PAS  less leukopenia/diarrhea/nausea/vomiting
• 1st normal sperm count (in pts with pre-RT normal values):
                     PAS: 13 mos (12.5-13.5 mos)
                     DL: 20 mos (12,5-30 mos)
          MRC TE 18: 30 Vs 20 Gy
•   Jones et Al, JCO 23:1200, 2005
•   1995-98: 625 pts (30 Gy: 313; 20 Gy: 312)
•   median fu: 61 mos
•   21 relapses: 30/20 Gy: 10/11; Pelvic 6/3 (1/5 DL, 8/16 PAS)
•   5yr rel-free survival:          30 Gy 97% (94.3-98.3%)
                                    20 Gy 96.4% (93.5-98%)
•   DS survival:                    30 Gy 1 AWD
                                    20 Gy 1 DOD
•   severe/moderate lethargy:       30 Gy 20%
                                    20 Gy 5%      p<.001
•   unability to carry out normal work at 4 wks
                                    30 Gy: 46%
                                    20 Gy: 28% p<.001
•   second cancer: 6 non-germ cell cancers, all in 30 Gy group
     MRC TE 19: Carboplatin Vs RT
•   Oliver et Al, Lancet 366:293, 2005
•   1996-2001: 1477 pts (30Gy/20Gy RT: 904; 1 course Carbo AUC 7: 573)
•   median fu: 4 yrs
•   65 relapses; RT/Carbo: 36/ 29; RP: 13% Vs 74%; Pelvic 31% Vs 0
•   3yr rel-free survival:         RT 95.9% (94.4-97.1%)
                                   Carbo 94.8% (92.5-96.4%)
•   DS survival:                   1 DOD following RT
•   Acute tox: thrombocytopenia             G1-2 RT 2% Carbo 12%
                           “                G3-4 RT 0 Carbo 4% p<.0001
                   dyspepsia                RT 17% Carbo 8%        p<.0001
•   Moderate/ severe lethargy:              RT 24%
                                            Carbo 7%               p<.0001
•   unability to carry out normal work at 4 wks
                                            RT:    38%
                                            Carbo: 19%             p<.0001
•   second cancer:         10 (RT) to 2 (carbo) new germ cell cancers
“Effect of radiotherapy volume and dose on
secondary cancer risk in stage I testicular
seminoma”.Zwahlen DR et Al, Int J Radiat Oncol Biol Phys,
2008;70:853
•   the secondary cancer risk (SCR) due to para-aortic (PA), dogleg field (DLF),
    or extensive field (EF) radiotherapy (RT) at different dose levels for Stage I
    testicular seminoma
•   organ equivalent dose concept with a linear, plateau, and linear-exponential
    dose-response model
•   estimated cumulative SCR for a 75-year-old patient treated with PA-RT at
    age 35 was 23.3% (linear model), 20.9% (plateau model), and 20.8%
    (linear-exponential model) compared with 19.8% for the general population
•   dependent on the model, PA-RT compared with DLF-RT reduced the SCR
    by 48-63% or 64-69% when normalized to EF-RT for PA-RT, the linear
    dose-response model predicted a decrease of 45% in the SCR, using 20
    Gy instead of 30 Gy
•   the SCR after PA-RT for Stage I seminoma is reduced by approximately
    one-half to two-thirds compared with DLF-RT; the SCR is expected to be
    equal or lower with 20 Gy than with 30 Gy
The long-term risks of adjuvant carboplatin
treatment for stage I seminoma of the testis.
Powles T et Al. Ann Oncol 2008;19:443

• 199 patients with clinical stage I seminoma
• 1 or 2 cycles of adjuvant carboplatin as a single agent
• follow-up: 0.1-20.1 years (median 9)
• no excess mortality compared with the age and sex-
  matched UK population with 95% confidence intervals
  (CIs) on their standardised mortality ratio (SMR) from
  0.36 to 1.83
• no significant increase in death from circulatory disease
  (SMR 1.44; 95% CI 0.39–3.69) or in incidence of second
  cancers [standardised incidence ratio (SIR) 0.96; 95% CI
  0.26–2.45])
RT: PAS Vs DL
Advantages                        Disadvantages
Reduction of acute toxicity       Increase of pelvic recurrences (right)?
Earlier recovery of fertility     Does a risk of late toxicities remain?
Simplification of treatment

RT: 20 Gy Vs 30 Gy
Advantages                        Disadvantages
Early physical recovery           Increase of recurrences (nonpelvic)?
Reduction 2° cancer (?)           Does a risk of late toxicities remain?

Carboplatin Vs RT
Advantages                        Disadvantages
Reduction of GI tox               Increase of hematological tox
Earlier physical recovery         Increase of retroperitoneal relapses (?)
Reduction of 2° cancer risk (?)   Too few data and too early for evaluation
Reduction contralateral cancer
                    THM
• Prognosis of stage I GCTs is excellent
  when proper treatments are administered
• Modern concepts must include
  consideration regarding ease of use and
  complexity of therapy, simplification of f-u,
  late relapses and toxicity (early and late)
       THM: non seminoma
• 3 choices: surveillance, RPLND, adjuvant
  chemotherapy (2 PEB)
• Beware of VI! (possibly review)
• Consider availability of resources and
  patient preference
• Consider aspects favoring patients
           THM: seminoma
• 3 choices: surveillance, adjuvant
  radiotherapy (PAS, 20 Gy), adjuvant
  chemotherapy (CBCDA 7 AUC)
• Data on CBCDA are too early to draw
  definitive conclusions on long term safety
• Consider availability of resources and
  patient preference
• Consider aspects favoring patients
Italian Germ-cell cancer study Group

            Since 2005!

				
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