Followup investigations under treatment to guide further treatment

1
Follow-up investigations under treatment to guide
further treatment

• Thomas Christoph Gauler
• Department of Internal Medicine (Cancer
  Research)
• Director Professor Martin Schuler
• West German Cancer Center
• University Hospital Essen, Germany

2
response evaluation - overview

• clinical symptom relief
• serum markers LDH, AFP, ß-HCG
• chest-X-Ray and abdominal ultrasonography
• computed tomography (CT)
• magnet resonance imaging (MRI)
• positron emission tomography (PET)

3
Case report

• 24-year old male
• extragonadal non-seminomatous germ cell tumor
  (NSGCT, chorioncarcinoma), 15 kg weight loss,
  gynecomastia, abdominal pain, PS 1
• 02/Nov/07 Tx pN3 M1 (PUL, BRA) S3, IIIC poor
  prognosis, LDH 475 U/l, ß-HCG 289.034 mIU/ml,
  AFP normal
• 02/Nov/07 10/Jan/08 1 x VIP and 3 x HD/VIP
  with PSCT
• Adequate early clinical response with weight
  gain, reslovement of gynecomastia and abdominal
  pain

4
Case report
24-year old male

Adequate tumor marker response with normalisation
of LDH following one course of standard dose VIP
5
Case report
09/Nov/07 25/Jan/08

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Case report
29/Oct/07 25/Jan/08

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Case report
29/Oct/07 25/Jan/08

06/Feb/08 RLA with total tumor necrosis (pCR),
ß-HCG 7,4 mIU/ml (19/Feb/08)
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Case report

• 07/Mar/08 increasing ß-HCG (28 mIU/ml) with
  further remission of the pulmonal metastasis
  (CT), no change of the residual brain mets
  right and a new unclear contrast agent
  enrichment left high parietal

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Case report

• 25/Mar/08 hemiplegia right due to left
  hemispheric intracranial
• hemorrhage, possibly metastasis (CT and MRT)
• 04/Apr/08 ß-HCG 861 mIU/ml
• 21/Apr/08 cerebral metastasectomy
  (chorioncarcinoma)

31/Mar/08
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response evaluation - overview

• clinical symptom relief
• serum markers LDH, AFP, ß-HCG
• chest-X-ray and abdominal ultrasonography
• computed tomography (CT)
• magnet resonance imaging (MRI)
• positron emission tomography (PET)

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clinical symptom relief

• easy to follow up when occur
• no costs
• subjective and not really measurable response
  parameter
• high variability of clinical symptoms possible
• not accepted for response evaluation

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response evaluation - overview

• clinical symptom relief
• serum markers LDH, AFP, ß-HCG
• chest-X-Ray and abdominal ultrasonography
• computed tomography (CT)
• magnet resonance imaging (MRI)
• positron emission tomography (PET)

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LDH

• unspecific tumor marker
• important prognostic factor in advanced GCT1
• elevated in 35 of all GCT1
• half-life-time is one day2
• easy measurable in daily routine laboratory
• increase under G-CSF stimulation possible

1IGCCCG JCO 1997 15594-603 2Lange et al J Urol
1981 128708-11
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LDH

• 38-year old male
• left scrotal NSGCT, 10 kg weight loss,
  vena-cava-inferior syndrom, abdominal pain, renal
  insufficiency, PS 1
• 01/Feb/08 T4 cN3 M1 (HEP) S3, IIIC poor
  prognosis, LDH 58479 U/l, ß- HCG 1261 mIU/ml,
  AFP normal
• 02/Feb/08 25/Apr/08 2 x VIP and 3 x HD-VIP
  with PSCT

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AFP and ß-HCG

• elevated in 80 of metastatic GCT (prognostic
  factor). AFP never increased in seminomas.1
• measured directly before each treatment cycle
  (falsely increased due to marker-release from
  necrotic tumor cells)
• acceptable half-life-time during chemotherapy
  (calculated satisfactory decline) AFP 7 days,
  ß-HCG 3,5 days2
• documented tumor marker increase during
  chemotherapy (very poor prognosis) ? salvage
  treatment3,4

1Bosl, GJ Man Oncol Therap 1995 349-54 2Lange
et al. J Urol 1981 128708-11 3Motzer et al.
JCO 1997 152546-52 4de Wit et al. Br J Cancer
1998 781310-15
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Value of decline-rate of ß-HCG and AFP during
chemotherapy
Mazumdar, M. et al. J Clin Oncol 2001 192534-41
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Value of decline-rate of ß-HCG and AFP during
chemotherapy
Survival of patients according to satisfactory or
unsatisfactory (A) AFP, (B) HCG, and (C) overall
marker decline
Mazumdar, M. et al. J Clin Oncol 2001 192534-41
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Value of decline-rate of ß-HCG and AFP during
chemotherapy
Mazumdar, M. et al. J Clin Oncol 2001 192534-41
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Value of decline-rate of ß-HCG and AFP during
chemotherapy
Survival for (A) good-, (B) intermediate-, and
(C) poor-risk patients according to satisfactory
or unsatisfactory overall marker decline
Mazumdar, M. et al. J Clin Oncol 2001 192534-41
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BEP vs BEPHDCT in intermediate or poor prognosis
GCT patients with elevated baseline markers who
have a satisfactory marker decline compared with
those who have an unsatisfactory decline
TTF
Motzer, R. J. et al. J Clin Oncol 2007 25247-56
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Early predicted time to tumor marker
normalization predicts outcome in poor prognosis
NSGCT

• data from 653 pts (139 of poor risk) with tumor
  markers obtained before chemotherapy and 3 weeks
  later.
• decline rate was calculated with a logarithmic
  transformation to express predicted time to
  normalization TTN TAFP 9 and THCG 6 weeks
  (cutoff point)
• also strong predictor in the multivariate analysis

Fizazi, K. et al. J Clin Oncol 2004 193868-76
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Control investigations - overview

• clinical symptom relief
• serum markers LDH, AFP, ß-HCG
• chest-X-ray and abdominal ultrasonography
• computed tomography (CT)
• magnet resonance imaging (MRI)
• positron emission tomography (PET)

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chest-X-ray and ultrasonography

• accepted for treatment monitoring of metastasis
• both are cost-effective and fully available
• X-ray of chest with low radiation burden (0,04
  mSv)
• X-ray limitation in measuring tumor boundaries,
  contrast and resolution
• US good soft tissue contrast, real-time image.
  But operator dependency limiting reproducibility

Barentsz et al. JCO 2006 243234-44
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Measure of response - RECIST

• simplistic in concept and execution (time-saving
  method)
• bone and soft tissue infiltration structures are
  excluded
• limitation in measuring tumor boundaries
• no provision for total volume in the presence of
  more accurate time-series volumetric measurement
  and better contrast agents
• morphologic changes are not considered

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response evaluation - overview

• clinical symptom relief
• serum markers LDH, AFP, ß-HCG
• chest-X-Ray and abdominal ultrasonography
• computed tomography (CT)
• magnet resonance imaging (MRI)
• positron emission tomography (PET)

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CT

• required and widely accepted for RECIST
  assessment in contrast to X-ray and US
• documentation of progression under chemotherapy
  in case of declining tumor markers (rare) for
  planning surgery (highly probable growing
  teratoma syndrome)1
• follow up of target lesions, which could not
  assessed by X-ray or US
• not necessary before end of first-line
  chemotherapy in case of satisfactory decline of
  tumor marker
• high radiation burden (chest 8.3 mSv,
  abdomen/pelvis 16 mSv)2

1Andre, F. et al. Eur J Cancer 2000 361389-94
2 Barentsz et al. JCO 2006 243234-44
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response evaluation - overview

• clinical symptom relief
• serum markers LDH, AFP, ß-HCG
• chest-X-Ray and abdominal ultrasonography
• computed tomography (CT)
• magnet resonance imaging (MRI)
• positron emission tomography (PET)

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MRI

• equipotent (sensivity) to CT in the assessment of
  metastasis in the chest/abdomen
• more sensitive in the assessment of brain or bone
  metastasis then CT during treatment (high
  resolution)
• used for specific questions (soft tissue
  structures, vessel infiltration) under or after
  treatment because of its high soft tissue
  contrast
• no radiation burden
• long examination time, costs, availability

Barentsz et al. JCO 2006 243234-44
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MRI - perspectives

• MR spectrometer (MRS), the radiofrequency
  receiver system, may predict survival or identify
  necrosis after treatment like in glioblastoma
• perfusion MR blood flow and volume, vessel size,
  permeability
• diffusion MR changes in water mobility may
  represent early tissue damage
• contrast agents like ferumoxtran-10 in lymph
  nodes
• DCE-MRI assessing tumor angiogenesis and the
  effects of antiangiogenic therapy

Sorensen JCO 2006243274-81 Hilton JCO
2006243293-98.
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response evaluation - overview

• clinical symptom relief
• serum markers LDH, AFP, ß-HCG
• chest-X-Ray and abdominal ultrasonography
• computed tomography (CT)
• magnet resonance imaging (MRI)
• positron emission tomography (PET)

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FDG-PET - background

• patients with favourable response frequently show
  negative PET scans after completion of therapy
• measurable quantitative changes (early decreased
  tumor glucose utilization) may occur already
  during therapy (early indicator for tumor
  response) and are excellently reproducable
• metabolic flare phenomenon, caused by therapy,
  plays only a role in the first hours after
  therapy
• accuracy of PET to predict response and survival
  has been demonstrated in larger clinical trials
  and different tumor types (GIST, lung cancer,
  lymphoma)
• However, the reported threshold values vary
  widely and not all studies have stratified
  patients by tumor size (affect the measured tumor
  FDG uptake)

Weber JCO 2006243282-92.
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FDG-PET Validation as an early marker to tumor
response

• standardize the acquisation and analysis of
  FDG-PET-scans
• define criteria for a metabolic response in
  FDG-PET (EORTC criteria, 1999)
• prospective data
• early identification of nonresponding tumors
  (e.g. 35 decrease in tumor FDG-uptake two weeks
  after start of induction-chemotherapy as
  criterion for histopathological response and
  survival)

Weber JCO 2006243282-92.
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MUNICON-trial

• used this information in a neoadjuvant
  phase-II-setting with adenocarcinomas of the
  esophagogastric junction
• metabolic non-responders (arm B) discontinue
  chemotherapy after two week evaluation and
  proceed to surgery, responders (arm A) receive
  neoadjuvant chemotherapy for 12 weeks before
  resection

Lordick et al. Lancet Oncol. 2007 8(9)797-805
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Early prediction of treatment response to
HD-salvage-CTx in relapsed GCT using FDG-PET

• small trial (n23) with FDG-PET-comparison after
  2-3 cycles of induction-CTx before HD-CTx in
  correlation with CT and tumor marker
• correctly predicted outcome of HD-CTx by
  PET/CT/tumor marker in 91/59/48.
• prediction of failure of HD-CTx
  (sensivity/specifity) PET 100/78, CT-monitoring
  43/78, tumor marker 15/100
• positive and negative predictive values of PET
  88/100
• compared with prognostic score PET was correctly
  positiv in all pts of the three risk groups who
  failed treatment.
• a negative PET correctly predicted a favourable
  outcome in the good and intermediate group

Bockemeyer et al. British J Cancer 2002 86506-11
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Conclusions

• unsaticfactory tumor marker decline or increase
  under chemotherapy correlates with poor prognosis
  and seems to predict CR, EFS and OS
• alternative treatment options (like HD-CTx) could
  overcome this predicted outcome (limitation only
  one prospective phase III trial)
• other potentially predictive investigations under
  treatment (like PET) are not yet established in
  GCT in larger series