Download Neuroendocrine tumours of the GI tract

An odyssey into the land of rare
tumours: adenocarcinoma of small
bowel and endocrine tumours
Monika Krzyzanowska, MD MPH
MOTP Half-day
March 27th, 2009
Objectives
• Review the management of the following
tumours with a focus on systemic therapy
and the role of medical oncologist in
management:
– Small bowel adenocarcinoma
– Neuroendocrine tumours of the GI tract
– Thyroid carcinoma
Small Bowel Neoplasms (SEER)
Type
Prevalence
Adenocarcinoma
45%
Neuroendocrine tumours
30%
Lymphoma
15%
Sarcoma
10%
Other
< 1%
Small Bowel Adenocarcinoma
Epidemiology (1)
• Extremely rare tumour (<< 1% of all
malignancies)
• Most common presenting symptoms:
– Abdominal pain
– Obstruction
– Bleeding
• Main risk factor - Crohn’s disease
Epidemiology (2)
• Most frequent site is duodenum (approx
50%) followed by jejunum & ileum
• About 1/3 present with metastatic disease
• Most common metastatic sites - liver and
peritoneum
Diagnosis
• Difficult to diagnose because of lack of
optimal non-invasive modalities to image
the small bowel
• Most frequently diagnosed intraoperatively,
by CT or at time of gastroscopy (duodenal
tumours)
• Emerging modalities – video capsule
endoscopy, PET scans
Staging (1)
Staging (2)
Prognosis
• Median overall survival in retrospective
series approximately 18 months; <12
months with metastatic disease
• 5-yr overall survival (all stage) about 25%
• Recurrences tend to be distal rather than
local
Surgery
• The only potentially curative option
• 5 yr survival 20-60%
• No definite standard type of surgery
(segmental resections  Whipple
procedure) although retrospective studies
suggest patients with proximal tumours may
do better after Whipple
Systemic Therapy (1)
• Lack of prospective data on the role of
chemotherapy in either the adjuvant or
metastatic setting
• Most information comes from retrospective
reviews usually from single institutions
• These suggest about 30% of patients receive
adjuvant tx
Systemic Therapy (2)
• Chemotherapy regimens have generally been
extrapolated from gastric, pancreas, stomach or colon
cancer protocols
• Commonly used agents:
–
–
–
–
5FU
Cisplatin
Irinotecan
Gemcitabine
• Response rates have been described (incl CR) and
studies suggest survival benefit but difficult to control
for selection bias given lack of prospective,
controlled trials
Systemic Therapy: PMH
Experience (N = 113*)
Regimen
N
ORR
Fluoropyrimidine alone**
15
13%
Gemcitabine+/-5FU**
17
33-50%
Platinum-based
7
43%
CPT-11
12
42%
Other
2
0%
*not all patients received chemo
**includes capecitabine
Adapted from Fishman et al, AJCO 2006
Small bowel adenoca:
Bottom line
• Role of adjuvant chemotherapy uncertain
• Chemotherapy may be worthwhile in
selected patients with advanced disease
• Optimal regimen not clear but gemcitabine
or irinotecan (single agent or in
combination with 5FU) probably best firstline choices
Neuroendocrine Tumours (NET)
of the GI Tract
Anatomic Classification
• FOREGUT
– Respiratory tract
– Thymus
– Stomach, pancreas &
proximal duodenum
• MIDGUT
– Jejunum, ileum,
appendix
– Ascending colon
• HINDGUT
– Transverse and descending
colon
– rectum
GI tract NETs: Epidemiology
• Majority arise in midgut
• Incidence increasing
• Appendix is the most common site followed by
small bowel
• Can be functional (ie. secrete various hormones
such as gastrin, hCG, serotonin) or non-functional
• Can be benign or malignant
• Most common metastatic sites are liver & bone
Pathology
• Classification is evolving
• Should be reviewed by a pathologist with
expertise in neuroendocrine tumours
• Special stains include:
–
–
–
–
Neuron specific enolase
Synaptophysin
Chromogranin
Mitotic count +/- Ki67 antigen to assess rate of
proliferation
• Grade of differentiation – may affect management
Grading proliferation of welldifferentiated NETs
Grade
G1
Mitotic Count (per Ki-67 Index
10 HPF)
(%)
<2
2
G2
2-20
3-20
G3
>20
>20
Rindi et al, Virchows Arch 2006; 449:399
Carcinoid Syndrome
• Syndrome associated with excess of serotonin,
histamine or tachykinins
• Symptoms/signs:
– Episodic flushing
– Diarrhea
– Cardiac disease (right sided valvular disease)
• Tends to occur when tumour in close contact with
systemic circulation:
– Liver metastases
– Bronchial or ovarian carcinoids
• Treatment consists of somatostatin analogues which
inhibit hormone release
Baseline Investigations (1)
• Depends in part on location
• Labs:
– Chromogranin A –not easily available
– Urine 5-HIAA (breakdown product of serotonin)
• Imaging
–
–
–
–
–
CT/MRI (contrast essential)
Octreoscan (somatostatin receptor scintigraphy)
Endoscopic U/S (pancreatic tumours)
+/- Bone scan
Standard PET (18F-fluorodeoxyglucose) not helpful;
better with other tracers (5-hydroxy-L-tryptophan), but
not easily available
Baseline Investigations (2)
• Other:
– 2D Echo in selected patients (symptoms
suggestive of carcinoid syndrome, murmur or
elevated 5HIAA levels)
Staging
• A TNM based system has been recently
proposed albeit not being yet used
Rindi et al, Virchows Arch 2006; 449:399
• Usually classified into:
– Localized
– Locoregional
– Metastatic
Prognosis
• Overall, 5 year survival approx. 67%
• Highly variable (usually measured in years),
correlated with:
–
–
–
–
Stage
Size (esp in appendiceal & rectal carcinoids)
Location
Differentiation
Management of
Recurrent/Metastatic NET
Management Overview
• Treatment depends on:
–
–
–
–
–
–
Symptoms
Presence/lack of hormone excess
Location of metastatic disease
Rate of growth
Histologic differentiation
Patient preference
Somatostatin Analogues
• Control hypersecretion of neuropeptides in foregut
& midgut carcinoids that express somatostatin
receptors
• Available as a short or long-acting injection
• Until recently was predominantly indicated for
symptom control and to prevent complications in
carcinoid syndrome
• Anti-tumour effects have been a matter of debate –
occasional responses have been described, disease
stabilization more common
• Tachyphylaxis can develop over time
Liver Only Disease
•
•
•
•
Surgical resection/debulking if feasible
Bland embolization
Chemoembolization
Radiofrequency ablation
Metastatic Disease not Amenable
to Local Tx
• Treatment depends on symptoms and rate of
clinical/radiologic progression
• For asymptomatic/slow growing tumours
consider octreotide (F/U q3-6 months)
• For symptomatic/rapidly growing tumours
may consider systemic therapy, preferably
as part of clinical trial
Poorly Differentiated Tumours
• Thought to be related to small cell
carcinoma of lung
• Usually treated with platinum-based
regimens often VP16/cisplatin
– RR up to 67% have been reported including
CRs (Moertel Cancer 1991)
Well-differentiated Tumours (1)
• Number of phase 2/3 studies over the last 30 yrs
• Less responsive to chemotherapy esp non–islet
cell tumours
• Usually treated with streptozotocin-based therapy
• Limited response to cisplatin/VP16 (<<20%)
• Limited activity of newer agents (gemcitabine,
taxanes)
Chemotherapy for welldifferentiated tumours
Regimen
RR (%)
References
STZ alone
36%
Moertel Canc Clin Trials 1980
STZ/5FU
23%-63%
Moertel Canc Clin Trials 1979
Moertel NEJM 1980
Engstrom JCO 1984
STZ/cyclophosphamide
26%
Moertel NEJM 1980
STZ/doxorubicin
69%
Moertel NEJM 1992
Doxorubicin
20%
Engstrom JCO 1984
Chlorozotocin
30%
Moertel NEJM 1992
FAC-S
(5FU/dox/cyclo/STZ)
29%
Bukowski Cancer 1987
Quality of Evidence
• Many methodologic concerns with existing
trials:
– Different patient populations
– Large numbers of inevaluable pts
– Assignment based on previous tx or comorbid
conditions in randomized studies
– Use of physical exam or biochemical response
to evaluate efficacy
Chemotherapy for welldifferentiated tumours
• Generally better RR in islet-cell tumours
• Whether survival advantage exists for
streptozotocin + doxorubicin vs streptozotocin +
5FU not clear:
– survival advantage for doxorubicin combination in one
study (2.2 vs 1.4 years STZ/dox vs STZ/5FU) Moertel
NEJM 1992
– survival advantage for 5FU combination in another
(24.3 vs 15.7 months STZ/5FU vs STZ/dox)
Sun
JCO 2005
Emerging Therapies
• Promising/ongoing:
– radiolabelled somatostatin & MIBG analogues +/chemo
• Ineffective:
– Endostatin
– Single agent thalidomide (more promising in
combination with chemotherapy)
– Imatinib
– Bortezomib
NET Bottom line (1)
• Consider whether curative/debulking
surgery warranted
• Recent evidence suggests that there is a role
for long-acting octreotide in many pts – not
just those with biochemical evidence of
hormone excess +/- symptomatic carcinoid
syndrome
NET Bottom line (2)
• Liver-directed therapies for patients with liver
predominant disease
• Consider chemotherapy in patients with
symptomatic disease not amenable to local tx:
– Streptozotocin-based for well-differentiated tumours
– Cisplatin/VP16 in poorly differentiated tumours
– Clinical trials!
Thyroid Cancer
Histologic Classification
Thyroid Cancer
Differentiated
Papillary
Follicular
Medullary
Anaplastic
Hereditary
Sporadic
Differentiated Thyroid Tumours
• Account for approximately 80-90% of all thyroid
malignancies
• Originate from follicular epithelial cells within the
thyroid
• Broadly split into papillary or follicular tumours
• Prognostic factors include age, size, histologic
grade, lymph node involvement
Medullary Thyroid Cancer
• Arise from the parafollicular C-cells of the neural
crest
• 70% sporadic
• 30% hereditary
– Familial medullary thyroid cancer not associated with
MEN
– MEN 2A (pheochromocytomas, hyperparathyroidism)
– MEN 2B (pheochromocytomas, neuromas)
Treatment of Early Stage Disease
DIFFERENTIATED
• Surgery
• Thyroid hormone
replacement
• +/- 131I
• +/- external beam
radiation therapy
MEDULLARY
• Surgery
• +/- external beam
radiation therapy
Metastatic Disease:
Differentiated Thyroid Cancer
• Approx 20% of patients will develop distant
metastatic disease
• Most common sites are lung and bone
• Survival extremely variable & correlated with age,
site of involvement, tumour burden & response to
iodine:
– Patients < 20 years of age: 100% 10 year survival
– Patients > 40 years of age: 20% 10 year survival
Schlumberger et al, J Nucl Med 1996;37
Metastatic Disease: Medullary
Thyroid Cancer (MTC)
• Incidence varies depending on type of MTC –
generally 5-20%
• Most common site is liver followed by lung &
bone
• Survival variable (5 year survival 80-90%) and
related to location of recurrence as well as type of
MTC
Recurrent Disease
DIFFERENTIATED
MEDULLARY
• Surgery
• 131I
• External beam radiation
• ?chemotherapy for 131I
refractory patients
• Surgery
• External beam radiation
therapy
• ?chemotherapy
Chemotherapy in Thyroid Cancer
• 1970 – 2009: < 20 clinical trials published of
cytotoxic chemotherapy in patients with advanced
thyroid cancer
• All but one of the trials were phase 2
• Sample size: 5-92 patients (median 20 pts)
• Main drugs:
–
–
–
–
Doxorubicin
Cisplatin
Dacarbazine
5-FU
Doxorubicin trials in thyroid cancer
Reference Agent
N Histology
Response
Rate
Droz
1984
Doxorubicin
14
Medullary
15%
Droz
1984
Cisplatin
14
Medullary
21%
Shimaoka
1985
Doxorubicin
Doxorubicin + cisplatin
41
43
Various
17%
26%
Williams
1986
Doxorubicin + cisplatin
22
Various
9%
Scherubl
1990
Doxorubicin + cisplatin +
vindesine
20
Various
6%
De Besi
1991
Doxorubicin + cisplatin +
bleomycin
22
Various
41%
JSTS
1995
Doxorubicin + cisplatin +
etoposide + peplomycin
17
Anaplastic
12%
Other agents in thyroid cancer
Reference Agent
N Histology
Response
Rate
Orlandi
1994
Dacarbazine + 5-FU
5
Medullary
60%
Wu
1994
Dacarbazine + vincristine +
cyclophosphamide
7
Medullary
29%
Schlumberger
1995
5FU + streptozotocin alt
5FU + dacarbazine
20
Medullary
15%
(55% SD)
Nocera
2000
5FU + dacarbazine alt
Doxorubicin + streptozotocin
20
Medullary
15%
(50% SD)
Leaf
2000
Etoposide
10
Differentiated
0%
Ain
2000
Paclitaxel
20
Anaplastic
53%
Santini
2002
Carboplatin + epirubicin +
TSH stimulation
14
Poorly
differentiated
37%
Cytotoxic Trials: Summary
•
•
•
•
Few studies
Small sample size
Heterogeneous populations
Mixed response assessment – radiologic +/biochemical
• Low response rates
• Toxic
Genetic Defects in Thyroid Cancer
Genetic Defect
Papillary
Follicular
Medullary
RET rearrangement
13-43%
-
-
-
-
30-50% sporadic
100% familial
BRAF mutation
29-69%
-
-
NTRK1
rearrangement
5-13%
-
-
RAS mutation
0-21%
40-53%
-
-
25-63%
-
0-5%
0-9%
-
RET mutation
PPAR rearrangement
P53 mutation
Adapted from Kondo et al, Nat Rev Cancer 2006;6
Tyrosine Kinase Inhibitor Targets
Agent
VEGF PDGF KIT
RET
BRAF Other
Axitinib
+
-
-
-
-
-
Gefitinib
-
-
-
-
-
EGFR
Imatinib
-
+
+
+
-
Bcr-Abl
Motesanib
+
+
+
-
-
-
Sorafenib
+
+
-
+
+
-
Sunitinib
+
+
-
+
-
-
Vandetanib
+
-
-
+
-
EGFR
XL184
+
-
+
+
-
C-MET
Published Trials
Reference
Agent
N
RR
SD
PFS
(months)
Ain
2007
Thalidomide
28*
18%
32%
6m
Pennell
2008
Gefitinib
27
0
24%
3.7
Sherman
2008
Motesanib
diphosphate
93*
14%
32%
9.2
Cohen
2008
Axitinib
60
30%
38%
18.1
Gupta
2008
Sorafenib
30*
23%
53%
18.2
Kloos
2008
Sorafenib
41
15%
56%
15
*evidence of disease progression prior to trial required
Trials Presented in Abstract Form
Reference
Agent
N
RR
SD
PFS
(months)
Cohen
ASCO 2008
Sunitinib
43
13%
68%
NR
Goulart
ASCO 2008
Sunitinib
18
NR
NR
NR
Ravaud
ASCO 2008
Sunitinib
20
10%
75%
NR
Ahmed
ASCO 2008
Sorafenib
18
NR
NR
NR
Axitinib: Overall Results
Cohen et al, J Clin Oncol 2008
Axitinib: Response by Histology
Cohen et al, J Clin Oncol 2008
Trials Specifically for Medullary
Thyroid Cancer
Trials Presented in Abstract Form
Reference
Agent
N
RR
SD
PFS
(months)
Wells*
ASCO 2007
Vandetanib
300mg OD
30
17%
50%
NR
Haddad*
ASCO 2008
Vandetanib
100mg OD
19
16%
63%
NR
Salgia
ASCO 2008
XL184
22
53%
47%
NR
*limited to hereditary population only
NR = not reported
Best Radiographic Response to XL184:
MTC Patients with ≥ 1 Post-Baseline Scan
40
% Tumor Change
RET TKIs
20
}
30
T, prior TKI therapy
V, prior vandetanib
M, prior motesanib
S, prior sorafenib
10
0
V
-10
-20
-30
-40
-50
S
V
V M
T
V
T V*
-60
• Available scan data for 28 patients with measurable disease (RECIST)
• Best overall RR = 55% (12/22 patients with ≥3 months of follow-up)
T
56 Year Old Male MTC Patient
Prior Therapies Include:
imatinib/dacarbazine/capecitabine & temozolomide
Baseline
XL184 treatment
Confirmed Partial Response
On Study Since January 2007
Changes in Thyroglobulin Levels
in Response to Axitinib
Cohen et al, J Clin Oncol 2008
Wells et al ASCO 2007;abst 6018
Wells et al ASCO 2007;abst 6018
Changes in Calcitonin vs. Maximal
Tumor Reduction
% Tumor Change
35
0
7 14 17 21 21 21 25 30 30 31 37 38 40 40 46 46 48
% Calcitonin Change
60
40
20
0
-20
-40
-60
-80
-100
Kurzrock et al, ATA 2008
Kurzrock et al, ATA 2008
Correlative Studies
• Emerging
• Initial work suggests that thyroglobulin
levels drop after initiation of therapy
?correlation to response
• Changes in calcitonin & CEA less clear
especially in the mixed histology trials
• Decreased circulating serum VEGF levels
• No clear genetic predictors thus far in MTC
Targeted Trials Thus Far
• Mixed bag of patients
– Often not histology specific
– Variable eligibility criteria
•
•
•
•
Small sample size
Single arm
Focus on tumour shrinkage
No information on patient relevant
outcomes
What Have We Learned?
• Histology matters
• Some agents may induce tumour shrinkage
in selected patients but stable disease (by
RECIST) most common
• Evidence of disease progression prior to
trial important to allow appropriate
interpretation of “stable disease”
What We Don’t Know
• How to identify patients at greatest risk of
progression
• Molecular predictors of response
• Role of tumour markers
• Does disease stabilization or shrinkage
translate into patient benefit
• Potential for chronic toxicity & its
management
Future Directions in Drug
Development in Thyroid Cancer
• Validation of response criteria/use of surrogate
markers
• Identification of patients most likely to benefit
• Combination with cytotoxic agents or
combinations of molecular agents
• Larger trials in differentiated cancers (randomized
trials)
• Duration of treatment
• Management of side effects
Thyroid Cancer Bottom Line
• Prognosis extremely variable therefore patient
selection for therapy challenging
• Limited role for cytotoxic chemotherapy –
obviously progressive disease, not eligible for trial
• Encouraging results with several new molecular
agents:
– ZD6474 & XL184 in medullary thyroid cancer
– axitinib, motesanib & sorafenib in differentiated
tumours
• Participation in clinical trials best option