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An odyssey into the land of rare tumours: adenocarcinoma of small
bowel and endocrine tumours
Monika Krzyzanowska, MD MPHMonika Krzyzanowska, MD MPH
MOTP Half-dayMOTP Half-day
March 27March 27thth, 2009, 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)
TypeType PrevalencePrevalence
Adenocarcinoma 45%
Neuroendocrine tumours 30%
Lymphoma 15%
Sarcoma 10%
Other < 1%
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
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*)
RegimenRegimen NN ORRORR
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 Adapted from Fishman et al, AJCO 2006Adapted from Fishman et al, AJCO 2006
**includes capecitabine
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 first-line choices
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 well-differentiated NETs
Rindi et al, Virchows Arch 2006; 449:399
Grade Mitotic Count (per 10 HPF)
Ki-67 Index
(%)
G1 <2 2
G2 2-20 3-20
G3 >20 >20
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 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 well-differentiated tumours
Regimen RR (%) ReferencesSTZ 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 well-differentiated 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!
Histologic ClassificationHistologic Classification
ThyroidThyroid CancerCancer
DifferentiatedDifferentiatedAnaplasticAnaplastic
MedullaryMedullary
PapillaryPapillary FollicularFollicular HereditaryHereditary SporadicSporadic
Differentiated Thyroid TumoursDifferentiated 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 CancerMedullary 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 DiseaseTreatment of Early Stage Disease
DIFFERENTIATEDDIFFERENTIATED
• Surgery
• Thyroid hormone replacement
• +/- 131I
• +/- external beam radiation therapy
MEDULLARYMEDULLARY
• Surgery
• +/- external beam radiation therapy
Metastatic Disease: Metastatic Disease: Differentiated Thyroid CancerDifferentiated 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 Metastatic Disease: Medullary Thyroid Cancer (MTC)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 DiseaseRecurrent Disease
DIFFERENTIATEDDIFFERENTIATED
• Surgery
• 131I
• External beam radiation
• ?chemotherapy for 131I refractory patients
MEDULLARYMEDULLARY
• Surgery
• External beam radiation therapy
• ?chemotherapy
Chemotherapy in Thyroid CancerChemotherapy 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 cancerDoxorubicin trials in thyroid cancerReference Agent N Histology Response
RateDroz
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 cancerOther agents in thyroid cancerReference Agent N Histology Response
RateOrlandi
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: SummaryCytotoxic Trials: Summary
• Few studies• Small sample size• Heterogeneous populations• Mixed response assessment – radiologic +/-
biochemical• Low response rates • Toxic
Genetic Defects in Thyroid CancerGenetic Defects in Thyroid Cancer
Genetic DefectGenetic Defect Papillary Papillary FollicularFollicular MedullaryMedullary
RET rearrangement 13-43% - -
RET mutation - - 30-50% sporadic
100% familial
BRAF mutation 29-69% - -
NTRK1 rearrangement
5-13% - -
RAS mutation 0-21% 40-53% -
PPAR rearrangement
- 25-63% -
P53 mutation 0-5% 0-9% -
Adapted from Kondo et al, Nat Rev Cancer 2006;6
Tyrosine Kinase Inhibitor TargetsTyrosine 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 TrialsPublished TrialsReference Agent N RR SD PFS
(months)
Ain 2007
Thalidomide 28* 18% 32% 6 m
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 FormTrials 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
Trials Presented in Abstract FormTrials 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
-60
-50
-40
-30
-20
-10
0
10
20
30
40
Best Radiographic Response to XL184:MTC Patients with ≥ 1 Post-Baseline Scan
• Available scan data for 28 patients with measurable disease (RECIST)• Best overall RR = 55% (12/22 patients with ≥3 months of follow-up)
% T
um
or
Ch
an
ge
V
T, prior TKI therapyV, prior vandetanibM, prior motesanibS, prior sorafenib
SV
V M
TV
TT
V*
RET TKIs
}
56 Year Old Male MTC PatientPrior Therapies Include:
imatinib/dacarbazine/capecitabine & temozolomide
Confirmed Partial ResponseOn Study Since January 2007
Baseline XL184 treatment
Changes in Thyroglobulin Levels Changes in Thyroglobulin Levels in Response to Axitinibin Response to Axitinib
Cohen et al, J Clin Oncol 2008
Changes in Calcitonin vs. Maximal Changes in Calcitonin vs. Maximal Tumor ReductionTumor Reduction
-100
-80
-60
-40
-20
0
20
40
60
% C
alc
ito
nin
Ch
an
ge
% Tumor Change
303035 21 25 40 4617 4838 46377 14 21 21 400 31
Kurzrock et al, ATA 2008
Correlative StudiesCorrelative 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 FarTargeted 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?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 KnowWhat 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 Future Directions in Drug Development in Thyroid CancerDevelopment 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 LineThyroid 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