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.