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%

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*)

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

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 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 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 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!

Thyroid Cancer

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

Axitinib: Overall ResultsAxitinib: Overall Results

Cohen et al, J Clin Oncol 2008

Axitinib: Response by HistologyAxitinib: Response by Histology

Cohen et al, J Clin Oncol 2008

Trials Specifically for Medullary Trials Specifically for Medullary Thyroid CancerThyroid Cancer

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

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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

Wells et al ASCO 2007;abst 6018

Wells et al ASCO 2007;abst 6018

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

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