15th annual advances in oncology october 10-11, 2014...
TRANSCRIPT
15th Annual Advances in Oncology
October 10-11, 2014
Lawrence H. Einhorn
Saturday, October 11
Keynote Lecture #1: “Complicated Issues for the Medical
Oncologist in Patients with Germ Cell Tumors”
Stock Shareholder: Amgen, Biogenidec
The presentation (does not include) discussion of the use of product(s) for which they are
not labeled (e.g., off label use) is still investigational.
COMPLICATED ISSUES FOR
THE MEDICAL ONCOLOGIST
IN PATIENTS WITH
GERM CELL TUMORS
LAWRENCE H. EINHORN
TOPICS
• Management of good, intermediate
and advanced disease
• Salvage therapy
• Clinical stage I and stage II
• Pearls
• Burden of the cured
“INTERNATIONAL GERM CELL CONSENSUS”
Advanced (14%) Intermediate (26%)
• PMNSGCT ● seminoma with non- pulmonary
• Non-pulm. visc mets visc mets
• AFP > 10,000 ● AFP 1,000 to 10,000
• HCG > 50,000 ● HCG 5,000 to 50,000
● LDH > 10XULN ● LDH 1.5 to 10 x ULN
Chemotx: BEP x 4 Chemotx: BEP x 4 or
or VIP x 4 BEP x 3 and EP x 1
at start of chemo at start of chemo
GOOD-RISK DISEASE:
BEP x 3 or EP x 4 ?
REASONS TO CHOOSE EP X 4
• Concern about pulmonary
fibrosis
• Perception that EP x 4 has a
higher cure rate than BEP x 3
REASONS TO CHOOSE BEP X 3
• Cisplatin remains the most toxic
drug due to cumulative
anorexia, nausea, vomiting,
neurotoxicity, ototoxicity
and sterility
• Data
BEP x 3 VERSUS EP x 4*
BEP x 3 EP x 4
(N = 127) (N = 124) p value
Adverse events 15 (13%) 27 (22%) 0.05
PFS 91% 86% 0.135
4 yr. surv. 96% 92% 0.096
*Culine S, et al.: Annals Oncology 18:917-924, 2007
RANDOMIZED TRIALS
IN GOOD-RISK DISEASE*
• 12 randomized trials reported
• 4 utilized EP x 4 with full dose etoposide (100 mg/m2
x 5); the durable response % was 81, 82, 86, and
87% with N = 414. Mean value 85%
• 5 trials evaluated BEP x 3 as a study arm; the
durable response % was 86, 87, 90, 91, and 92%
with N = 789. Mean value 90%
• There were no studies demonstrating numerical
superiority in a non-bleomycin arm
*Feldman, Bosl, et al.: JAMA 299:672-684, 2008
WHICH PATIENTS SHOULD
GET EP x 4?
• Serum creatinine > 2 mg%
• Inherent significant lung disease
• Age > 50
EUROPEAN CONSENSUS ON
DIAGNOSIS AND TREATMENT OF
GERM CELL CANCER*
“for patients with good prognosis
disease, according to IGCCCG criteria,
standard treatment is BEP x 3”
*Schmoll HJ, et al.: Ann Oncol 21:147-154, 2010 (suppl 5)
INTERMEDIATE RISK TESTIS CANCER
• Definition:
• hCG 5,000 – 50,000
at start of chemotherapy
• AFP 1,000 – 10,000
• LDH 1.5 – 10X ULN
• Bone, liver, CNS (seminoma only)
• Optimal therapy unknown
INTERMEDIATE RISK
• Accounts for 25-30% of cases – decreasing
incidence
• Most guidelines recommend BEP x 4 or
similar therapy for all cases of intermediate
risk
• Recommendations based upon IGCCG
retrospective analysis of cases from 1975 to
1990; this provided 3 prognostic categories.
Therapies included inferior regimens (PVB,
VAB, EP, carbo substituted for cisplatin)
INTERMEDIATE RISK: CASES
1. Serum LDH 3 x ULN, but hCG, AFP, and
C.T. scans normal
2. Serum AFP 1,000, hCG normal, 4 cm
RPLN and normal chest C.T.
3. Serum AFP 2,000, 4 cm RPLN and 3
separate 1-2 cm pulmonary metastases
4. Serum AFP 2,000 hCG 45,000, 4 cm
retroperitoneal mass and innumerable
pulmonary metastases
INTERNATIONAL GERM CELL
CONSENSUS CLASSIFICATION:
POOR PROGNOSIS DISEASE
• Non-seminoma
- Mediastinal primary
- Non-pulmonary visceral metastases
- AFP > 10,000 ng/ml
- hCG > 50,000 iu/l
- LDH > 10 x normal
JCO 15:594-603, 1997
POOR-RISK GERM CELL TUMORS:
INDIANA UNIVERSITY*
• Retrospective review of 237 consecutive patients seen from 1990
to 2011
• 100 patients had hCG > 50,000, 57 AFP > 10,000
• 63 PMNSGCT, 107 nonpulmonary visceral mets and 95 had more
than 1 criteria for poor-risk disease
• 164 (68%) received BEP or VIP x 4
• Statistically inferior PFS for nonpulmonary visceral mets and
multiple criteria for poor-risk
• Overall survival worse only for PMNSGCT (p = 0.0006) reflecting
salvage therapies in all other categories
• Only 2 patients (1%) had treatment-related mortality
*Adra, et al.: Proc ASCO, 2014
POOR-RISK: INDIANA
No. Pts. 237
Cont. NED 142 (59.9%)
Currently NED 175 (73.8%)
PFS: SINGLE VS. MULTIPLE CRITERIA FOR PRGCT
p value = 0.03
n = 142
n = 95
p value = 0.04
n = 130
n = 107
PFS: NPVM VS. NO NPVM
OS: PMNSGCT VS. TESTIS/RETROPERITONEAL
n = 95
p value = 0.0006
n = 172
n = 63
SALVAGE THERAPY OPTIONS
• Surgery
• Cisplatin + ifosfamide combination
chemotherapy
• No progression within 4 weeks of BEP
• Add agents not previously utilized
–Vinblastine + ifosfamide + cisplatin (VeIP)
–Paclitaxel + ifosfamide + cisplatin (TIP)
• High dose chemotherapy
• Carboplatin + etoposide
• Breast cancer failure versus testis cancer success
CONVENTIONAL VS. HIGH
DOSE SALVAGE CHEMOTHERAPY*
• Retrospective international evaluation of second-
line chemotherapy in patients with prior cisplatin
combination chemotherapy
• Total of 1,594 patients (773 received standard
dose salvage chemotx and 821 high dose chemotx)
• Prognostic variables assessed and patients
grouped into low, intermediate of high risk
disease
* JCO 28:4906-4911, 2010
FIRST-LINE SALVAGE CHEMOTHERAPY*
No. 2 yr. 5 yr.
Pts. PFS (%) survival (%)
Conventional dose 773 27.8 40.8
p< 0.001 p< 0.001
High dose 821 49.6 53.2
1,594
*Lorch A, et al.: JCO 29:2178-2184, 2011
CONVENTIONAL REGIMEN
No. 2 yr. 5 yr.
Pts. PFS (%) survival (%)
TIP 90 35.6 46.3
p< 0.083 p< 0.377
Other 683 26.8 40.2
CONVENTIONAL DOSE AND
SEQUENTIAL HIGH DOSE REGIMENS
No. 2 yr. 5 yr.
Pts. PFS (%) survival (%)
TIP 90 35.6 46.3
p< 0.083 p< 0.377
Other 683 26.8 40.2
Sequential
transplant 413 55.0 60.6
• Carboplatin 700 mg/M2 x 3 (2100 mg/M2)
· We do not use AUC
• Etoposide 750 mg/M2 x 3 (2250 mg/M2)
• Double transplant
HIGH DOSE SALVAGE
CHEMOTHERAPY IN GERM CELL
TUMORS
SALVAGE CHEMOTHERAPY
WITH PBSCT: RESULTS*
No. pts. No cont. NED (%)
Entire series 184 116 (63%);
Second-line Tx 135 94 (70%)
Third-line or later 49 22 (45%)
Seminoma 35 26 (74%)
Platinum refractory 40 18 (45%)
*Einhorn LH, et al.: NEJM 357:10-18, 2007
SALVAGE HIGH DOSE
CHEMOTHERAPY: SEMINOMA*
• Retrospective review of 48 consecutive patients with
pure seminoma who received high dose chemotherapy
with carboplatin + etoposide with peripheral blood stem
cell transplant from 2/96 to 6/06
• 36 of 48 (75%) continuously NED, including 22 of 24
receiving this therapy as initial salvage chemotherapy.
MFU 46 months (range 25-131 months)
• 4 of 48 (8%) treatment-related mortality, all in patients
with 2 or more prior chemotherapy regimens
* Agarwala et al.: Amer J Clin Oncol 34:286-288, 2011
TESTIS CANCER – STAGES
• Stage I - Involvement testis only
• Stage II - Testis and
retroperitoneal nodes
• Stage III - Disseminated disease
MEDICAL ONCOLOGIST VIEW OF
CLINICAL STAGE I
• Path review, careful radiographic assessment
and review marker data
• Special considerations:
a) PNET
b) elevated serum hCG or AFP – no
need to rush to judgment, but wait
to see if markers normalize
OPTIONS FOR CLINICAL
STAGE I SEMINOMA
• XRT
• Carboplatin AUC 7
• 1 vs. 2 courses
• Surveillance
RISK OF SECOND CANCERS IN SEMINOMA
PATIENTS TREATED WITH XRT*
• 2,703 survivors of CSI seminoma from UK and Norway
treated with infradiaphragmatic XRT
• Median F/U was 18 years
• 385 second cancers were reported in 354 men; mainly
gastric, pancreas, and bladder
• The excess of second cancers was statistically significant
(IR 1.31; 95% C.I. 1.2-1.5)
• “Infradiaphragmatic XRT is associated with a
significant excess of second cancers; policies for treating
stage I seminoma should be revised”
*Horwich A, Fossa S, et al.: Proc ASCO 28:351, 2010
SECOND MALIGNANCIES AFTER XRT
FOR CLINICAL STAGE I SEMINOMA*
• SEER data from 1973-2000 identified 5,994 clinical
stage I patients with seminoma treated with XRT
• 19% increase in second primary malignancies
compared to general population
• Increased risks for thyroid cancer, pancreatic cancer,
urothelial malignancies, leukemia and NHL
• Cure rate with orchiectomy alone 80-85% and only
1% will ever die of seminoma when surveillance chosen
*Lewinshtein D, et al.: BJUI 109:706-712, 2011
SURVEILLANCE FOR
CLINICAL STAGE I SEMINOMA*
• 1,822 patients in Danish National Study
• MFU 15.5 years
• 355 of 1,822 (19.5%) relapses
• 216 (61%) treated with XRT; 24 subsequently
required chemotherapy
• Disease specific survival 99.5%
*Mortensen MS, et al.: Proc ASCO, 2013 (abstr #4502)
CLINICAL STAGE I SEMINOMA:
SWENOTECA
• 839 patients with clinical stage I seminoma
• Risk factors were invasion of rete testis an tumor
size > 4 cm
• Relapse rate with surveillance only 3% if no rete
testis involvement and tumor < 4 cm compared to
22% for 1-2 risk factors
• Relapse rate with adjuvant carboplatin 6.2%
• Carboplatin, like cisplatin, remains detectable
10-20 years after administration
CLINICAL STAGE I OPTIONS
NSGCT
• RPLND
• nerve-sparing
• Surveillance
• Primary chemotherapy
• BEP x 2
• BEP x 1
BEP x 1 versus RPLND – CSI NSGCT
• 347 evaluable patients randomized from 9-96
through 2-05
• Median F/U 56 months (range 15-114 months)
• 42.7% of patients had vascular invasion
• 36 of 173 RPLND patients had
pathological stage II (20.9%). Stage II
patients all received 2 courses of adjuvant
BEP
BEP x 1 VERSUS RPLND: RESULTS
• 13 of 173 recurrences (7.6%) RPLND versus 2
of 174 (1.1%) with BEP x 1 (p = 0.0033)
• All RPLND relapses were pathologic stage I
patients who relapsed at median of 3.3 months
(range 1-17 months); 5 relapses in
retroperitoneum
• 60 month teratoma relapse in RPLN and 15
month marker relapse with BEP x 1
• All 347 patients currently NED
*Albers P, et al.: J Clin Oncol 26:2966-2972,2008
SURVEILLANCE FOR
CLINICAL STAGE I NSGCT*
• From 1999-2009, 1,168 patients observed
• MFU 63 months
• 256 (22%) relapses; 48% if vascular invasion and
14% if no vascular invasion
• Median time to relapse 6 months
• 90% of relapses good-risk and 8% intermediate-
risk
• Disease specific survival 99%
*Kollmannsberger CK, et al.: Proc ASCO 2013 (abstr 4503)
ACTIVE SURVEILLANCE IS THE
PREFERRED APPROACH TO CLINICAL
STAGE I TESTICULAR CANCER*
• 22 authors with experience in management
of testicular cancer
• Authorship included medical oncology,
radiation oncology, and urology
• 17 institutions in 7 different countries
represented
*J Clin Oncol 31:3490-3493, 2013
SURVEILLANCE
Clinical Stage I
•NCCN guidelines and frequency
of tests
•Size of retroperitoneal node, not an
independent prognostic variable
•Chest C.T.
•Pelvic C.T.
CLINICAL STAGE I NSGCT ON
SURVEILLANCE: FOLLOWUP (NCCN 2012)
Markers,
Year chest x-ray, and H&P Abd. C.T.*
1 1-2 months 3-4 months
2 2 months 4-6 months
3 3 months 6-12 months
4 4 months 6-12 months
5 6 months 12 months
6+ annually 12-24 months
*11 to 17 CT scans
MEDICAL ONCOLOGIST VIEW
OF CLINICAL STAGE II
• Size criteria: transverse diameter > 3 cm.
• Orchiectomy pathology
• Elevated markers
FOLLOWUP FOR TESTIS CANCER
• Clinical stage I seminoma
• Clinical stage II non-seminoma
• Post-chemotherapy F/U
• RPLND teratoma
• Beyond 5 years
• Second primary
• Late consequences of chemo
• Late relapse
• General health
TESTICULAR CANCER PEARLS (jewels)
• Tumor marker
•AFP 8-25 Ng/ml
•Initial hCG > 50,000
•LDH
•False positive hCG and AFP
•Risk stratification based upon pre-
orchiectomy hCG and AFP
SERUM AFP
• Half-life 5 days (surgery versus chemotx)
• Hereditary elevation of serum AFP
• Yolk sac tumor or embryonal cell CA
• Liver disease, liver metastases,
adenocarcinomas
• AFP levels 8-25 usually insignificant (Albany – JCO 32:2114-2115, July, 2014)
SERUM hCG
• Half-life 18-24 hrs. (surgery versus
chemotx)
• Marijuana
• Cross reactivity with LH
• Mononucleosis
• Large cell lung CA, melanoma, bladder
CA, G.I primaries
SERUM LDH
• Non-specific – not a “tumor marker”
• Elevated in many conditions, including
after Neupogen or Neulasta
• Intermediate: LDH 1.5 – 10 x ULN
• Advanced: LDH > 10 x ULN
• Should never use LDH as sole criteria for
risk stratification
LATE CONSEQUENCES OF THERAPY
● second malignancies
· etoposide and leukemia
· platinum is still present 10-20
years after therapy
● cardiovascular disease
● infertility
● hypogonadism
● late relapse
ASSOCIATION OF LONG-TERM EXPOSURE TO
CIRCULATING PLATINUM WITH ADVERSE LATE
EFFECTS IN TESTIS CANCER SURVIVORS
• Three serum and 24 hour urine specimens
collected to measure platinum levels at several
time points (median 5 years; range 1-13 years)
post-chemotherapy
• Circulating platinum still measurable 10 years
after completion of therapy
• Higher circulating platinum levels associated
with hypertension and paresthesia
• *Boer H, et al.: Proc ASCO 30:2012 (abst 4528)
LONG-TERM SERUM PLATINUM
CONCENTRATIONS*
• 169 cisplatin treated testis cancer patients
completed validated questionnaires about
ototoxicity and neurotoxicity
• Serum platinum measured by mass spectometry
• Higher Scale for Cisplatin Induced Neuropathy
(SCIN) scores associated with highest serum
platinum levels 5 to 20 years after chemotherapy
• Toxicity also related to age and total cisplatin
dose
*Sprauten M, et al.: J Clin Oncol 30:300-307, 2011
GENETIC SUSCEPTIBILITY AND BIOMARKERS
OF PLATINUM-RELATED TOXICITIES
• 9 institutions will participate
• Objective is to evaluate genetic susceptibility to long-
term platinum toxicity
• Identity single nucleotide polymorphisms
associated with neuro- and ototoxicity
• Sample size > 3,000 patients
• Collect data on other variables such as tobacco and
alcohol use, diet, exercise and other variables to provide
data for future prospective studies of the genetic
underpinnings of other long-term cisplatin toxicities
PREVENTATIVE STRATEGIES
• Second malignancy
• XRT clinical stage I seminoma
• Etoposide Dosage
• Cardiovascular complications
• Metabolic syndrome and hypogonadism
• Smoking cessation, obesity, lipid profile, B.P.
• Fertility
• Nerve-sparing retroperitoneal lymph node dissection
• Sperm banking and testis sperm extraction
• Long-term followup
• Late relapse or second primary
• Smoking cessation, healthy lifestyle, hypogonadism, lipid
profile, B.P.
POSSIBLE REASONS FOR SUCCESS
IN TESTICULAR CANCER
• Rapidly, proliferating tumor in young
patient population
• Chemosensitive in tumor with high C.R. rat
• Availability of tumor markers to help
define response.
• Surgical resection of persistent disease post-
chemotherapy
• Very low relapse rate
REASONS FOR LOW RELAPSE RATE
• Testis patients immunocompetent
• Germinal epithelium may be less prone to somatic
mutations
• Absence of mutated p53
• Absence of MDR gene
• “Minimal residual-disease” might be biologically
inert teratoma
• Germ cell tumor cells have a reduced capacity for
nucleotide excision repair due to cisplatin-induced DNA
damage with no overexpression of ERCC-1.