State-of-the-art approach in selective curable tumors: germ cell tumors
Professor Gordon Rustin Director of Medical Oncology Mount Vernon Cancer Centre Northwood Middlesex UK
Radical inguinal orchidectomy is standard practise; Consider Partial Orchidectomy if: • • • • •
Bilateral testicular tumours Single testicle Atrophic contralateral testis Small localised tumour Patient made aware that despite chemotherapy and or radiotherapy, high chance of infertility and need for HRT
Testis-preserving surgery in bilateral testicular germ cell tumours. Heidenreich A, Höltl W, Albrecht W, Pont J, Engelmann UH. Br J Urol. 1997 Feb;79(2):253-7
13 patients 6-30 mm diameter tumours Six of 13 patients 20 Gy for CIS and five patients had adjuvant local therapy. 13 patients free of disease at 62 months median follow-up. one patient local recurrence at 9 months but after orchidectomy free of disease at 156 months. luteinizing hormone and testosterone within the normal range in all patients and no androgen substitution was necessary.
Problems associated with partial orchidectomy • Despite Heidenreich data most patients receiving 20Gy develop androgen failure • Reducing to 16Gy risks tumour recurrence • Need to biopsy 2 years after therapy to exclude CIS • Should speak with oncologist before attempting partial orchidectomy • Bank sperm before operation
Why it is important to start chemotherapy quickly Germ cell tumours have potential volume doubling time of less than 1 week And potential HCG doubling time of less than 2 days A delay can therefore lead to organ failure but more likely can result in a worsening of prognosis
January 1987 Jan 87
February 1987
March 1987
Consider chemotherapy before orchidectomy for potential germ cell tumour if Patient has elevated HCG and or AFP and typical disease distribution and Has evidence of widespread metastases and Is breathless or has other evidence of impending organ failure
Stage 1 seminomas About 80% of seminomas are stage 1
Relapse on surveillance 29% if > 4cm and rete testis involved 12% if neither of above Vascular invasion only risk factor on univariate analysis
Current Management of Stage 1 Seminoma 20Gy in 10# to para-aortics
85% spared therapy
Cons Requires motivation of patient and oncologist Not suitable for some Can be stressful More hospital visits More aggressive therapy on relapse
Management Options for Stage 1 Nonseminomatous germ cell tumours Surveillance RPLND Adjuvant chemotherapy Patients should be made aware of the different management options Deciding which option depends upon histology, prognosis, geography, personality, reliability, bias of the doctor, but most importantly the patient
Surveillance for Nonseminomatous germ cell tumours
relapse rate Overall
30%
Lymphovascular invasion
40%
No risk factors
10-15%
(present in 47%)
Relapse-free rate by allocated CT schedule in TE08 trial 1.0 0.9 0.8
Relapse-free rate
0.7
Log rank
0.6
2 CT group – median relapse time is 4 months 5 CT group – median relapse time is 5 months
0.5
p-value = 0.21
0.4 1 Yr RFR (95% CI)
2 Yr RFR (95% CI)
2 CT scans
88.4% (83.6% - 91.8%)
84.7% (79.5% – 88.8%)
5 CT scans
81.0% (74.1% - 86.2%)
79.6% (72.6% – 85.1%)
0.3 0.2 0.1 0 0
12
24
36 48 60 Months from orchidectomy
72
84
Rustin et al J Clin Oncol 25: 1310-15, 2007
Risks of excess CT scans •Typical chest CT has an associated radiation dose equivalent to 400 chest X-rays (8 vs 0.02 mSv) (Royal College of Radiologists, 1998) •Whole trunk CT produces dose of 10 to 30 mSv •Typical whole trunk CT scan associated with a 1:1000 risk of cancer/leukaemia
Adjuvant chemotherapy for high risk stage 1 NSGCT Relapse free rate at 2 years 98% in 114 patients after 2 courses cisplatin 100 mg/m2, etoposide 360 mg /m2, and bleomycin 30 mg
Unclear if 1 course is sufficient
Retroperitoneal lymph node dissection for stage 1 NSGCT If pathological stage 1 risk of relapse 50 000 iU/L or LDH> 10XULN
16% non-seminoma 5yr PFS 41% 5yr OS 48%
No patients classified as poor prognosis
Characteristics found at staging that may alter management Mediastinal primary or Non-pulmonary visceral metastases Place patient into intermediate prognostic group if seminoma or poor prognostic group if non-seminoma according to International Germ Cell Consensus Classification
Management of Metastatic seminoma 6 year DFS after modern radiotherapy in 94 patients IIA – 95%,
IIB – 89%
3 courses of BEP or 4 courses of EP offer cure in >95% stage II-IV
Management of Metastatic seminoma Single agent carboplatin not currently recommended as 13% relapse rate in 108 patients
Royal Marsden exploring carboplatin followed by 35Gy as 3% relapse rate in 33 patients
Should intermediate or poor prognosis patients receive standard BEP or more aggressive chemotherapy?
Options for treating patients with intermediate or poor prognosis • Use more aggressive / dose dense regimens such as POMB/ACE, CBOP/BEP, GAMEC, TIP • Early change of therapy if inadequate response • High dose chemotherapy
Results of Chemotherapy for Advanced or Poor Prognosis GCT Regimen
Definition of Poor Prognosis
No of Patients
Various
IGCCCG
150
5 yr PFS
53
75-90
BEP/EP
MRC
185
1 yr FFS
60
84-94
Indiana
145
2 yr FFS
64
87-92
IGCCCG
92
3 yr O.S.
75
77-95
High dose VIP
Indiana
147
2 yr PFS
75
93-97
PEBV with high dose
Gustav Roussi
57
2 yr O.S.
60
88-91
IGCCCG
54
3 yr PFS
83
89-2000
VIP POMB/ACE
CBOP/BEP
Criteria
Outcome %
Years Treated
Which residual masses after chemotherapy require surgery? • Enlarging masses ? Growing teratoma • Masses >1cm if NSGCT • If pure seminoma and residual mass consider watching, radiotherapy or surgery • Remember to remove abnormal testicle as could contain occult tumour
Why do we follow-up patients who have had germ cell tumors? • To detect relapse: in the belief that earlier detection improves chance of cure • To detect contralateral testis tumors • To manage late toxicity • For reassurance, support and counselling • To collect data
Investigations to be performed at 2, 5 and 10 years to detect late effects of therapy for germ cell tumors Blood pressure Creatinine Fasting cholesterol, HDL, LDL , triglycerides and glucose FSH, LH and testosterone ? Hip examination ? Osteoporosis screen
Stop Smoking
Approaches to Management of germ cell tumours relapsing after chemotherapy • Consider why they relapsed • Is there a surgically resectable mass? • Is there different chemotherapy with a >50% chance NED? • What is the prognostic score? • Are there other co-morbid factors? • Consider high dose therapy with stem cell transplant
Disease-free Survival after High Dose Chemotherapy for relapsed germ cell tumour
Einhorn L et al. N Engl J Med 2007;357:340-348
Conclusion Virtually all patients with stage 1 germ cell tumours should be cured.
The challenge is to improve the cure rate of those with advanced disease closer to 100% and minimise early and delayed toxicity
Possible discussion slides
Second cancers among 40576 long term survivors of testicular cancer Travis et al JNCI 2005;97:1354-65
Life insurance for patients treated for germ cell tumours Time without
Time to standard
Extra/£1000 yr3-4
Seminoma stage1
1 year
4 years
£5
Non-seminoma stage 1
1 year
6 years
£10
£5
Stage 2 A/B
2-3 years
9 years
£10
£5
Stage 2 B, stage 3
3 years
9 years
£15
£10
Stage 4, intermediate and poor risk
3-4 years
9 years
£20
£15
Temporary loading usually lasts 3-6 years Provided by Graham Jones Underwriting Development Product Management & Development - Protection Direct line: 01793 505736 (internal: 5736) Email:
[email protected]
Extra year 5-6
Questions related to follow-up of patients with germ cell • How many different follow-up schedules should be running? • Could follow-up be nurse led? • Is AFP necessary if pure seminoma? • Is LDH of value in follow-up? • Is Chest X-Ray necessary if no lung metastases at time of treatment for metastases?
First indication of relapse in TE08 stage I surveillance trial Markers
28
42%
Markers + palpable mass
1
1%
Markers + abdo mass
2
3%
Abdominal CT
26
39%
Chest X-ray
5
8%
Chest CT
1
1%
Chest + abdo + pelvic CT
4
6%
Rustin et al J Clin Oncol 25: 1310-15, 2007
