JOURNAL READING

VS鄧豪偉醫師 /R4洪逸平

Patient Profile

Age: 58 y/o Gender: Female Diagnosis: Adenocarcinoma of rectum,

pT3N2b(12/21)M1, stage IV, with limited pelvis seeding, liver and lung metastasis

s/p LAR + BSO + resection of limited pelvis seeding, Port-A insertion on 2010/6/9 s/p FOLFOX-4 *6 (2010-9-20) with progessive disease s/p 2 cycle of FOLFIRI on 2010/10/19

Image Study

2010/10/20 CT 2010/11/01 MR

Clinical Course

s/p whole brain R/T with 3600cGy/12fractions during 2010/11/3-11/18 s/p xeloda (2010/10/30) s/p Xeliri x3, 2010/11/26-2011/01/07 s/p cetuximab with xeliri x5, 2011/1/21-2011/3/30 , with lung, liver metastasis progression

2011/4/30 CT

Clinical course

s/p Xeliri x4, 2011/4/13-2011/5/25 s/p Xeliri x5, 2011/6/16 s/p Xeliri x6, 2011/7/1 +Avastin with brain metastasis in regression but liver and lung mets mets in progression s/p Avastin + DTIC + XELIRI, C1 on 2011/10/06

2011/8/11 CT

2011/8/12 CT 2011/10/5 CT

Clinical Course

UGI bleeding, pneumonia, and ARDS developed

She was transferred to Hospice and was expired on 2011/11/13

COLON CANCER WITH BRAIN METASTASIS

鄧豪偉醫師 /R4洪逸平

Outline

Case presentation Introduction of metastatic brain tumor Prognostic factor of brain metastasis Treatment of colon cancer with brain

metastasis Conclusion

Metastatic Cancer in BrainMolecular Risk Factors

Mediators of cancer cell to pass BBB: COX2 (also known as PTGS2), the EGF receptor (EGFR) ligand HBEGF α -2,6-sialyltransferase ST6GALNAC5

Expression of the integrin αvβ3 Increase metastatic potential Promote angiogenesis

CXCL12(stromal cell-derived factor 1a) ligand of the CXCR4 chemokine receptor expressed in the brain

Nature 459(7249), 1005–1009 (2009).

Proc. Natl Acad. Sci. USA 106(26),10666–10671 (2009)

Semin. Cancer Biol. 14(3), 181–185 (2004).Clinical Colorectal Cancer, Vol. 8, No. 2, 100-105, 2009

Possibly risk factors of Brain Metastasis in Colorectal cancer

The majority of patients with brain metastases had concomitant systemic metastases, especially to lung (72.2% with lung metastases)

Extended treatment options resulting in improved survival for patients with metastatic CRC was associated with as much as 3% increased incidence of brain

J Neurooncol (2011) 101:49–55

Prognostic factors

Prognostic Factor of colon cancer with Brain metastasis

RPA class Size and number of metastasis Treatment

RTOG Recursive Partitioning Analysis(RPA)

The Radiation Therapy Oncology Group (RTOG) randomized 445 patients with brain metastatic tumor

The patients were subgrouping into 3 classes (RPA class I, RPA class II, RPA class III)

RTOG Recursive Tree

Int. J. Radiation Oncology Biol. Phys., Vol. 47, No. 4, pp. 1001–1006, 2000

KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA

Survival by RPA class from the RTOG database

Class I median survival 7.1monthClass II median survival 4.2 months

Tumor Biol. (2011) 32:1249–1256

Multivariate predictors of survival in patients with brain metastases from colorectal cancer

J Neurooncol (2011) 101:49–55

Treatment of brain metastasis in colon cancer

Conventional TreatmentWhole Brain radiation therapy

WBRT had been standard treatment for brain metastasis since 1950s, recommended for multiple metastasis

May extend the median survival from 1-2 to 3-7 months

Conventional TreatmentWhole Brain radiation therapy

The most commonly used WBRT schedule has been 30 Gy in ten 3 Gy fractions

Response rate: 60% Tumor shrinkage after RT correlated with

better survival and neurocognitive function

Radiosensitizers(efaproxiral, topotecan or motexafin gadolinium) may be tried

Symptomatic treatment

Anti-convulsant: if symptomatic convulsion. Prophylactic use

is not recommended Corticosteroid (Dexamethasone, up to

30mg/day): reduction of brain edema, rapidly Improve

of neurological function and quality of life

Surgery

Surgery is recommended to remove single metastasis if The primary lesion is under control The lesion is accessible The lesion is symptomatic or life-

threatening No more than 3 tumors should be

removedJ. Neurosurg. 79(2), 210–216 (1993)

Stereotactic radiosurgerygamma knife surgery

Small, well-collimated beams of ionizing radiation to ablate cerebral metastases of 3–4 cm or smaller

Advancements in 3D computer-aided planning and the high degree of immobilization have minimized the amount of radiation that passes through healthy brain tissue

An alternative to surgery and WBRT Main advantage: for small lesions(2.5-3cm) not

amendable by surgery or for pts not suitable for surgery

Tumor shrinkage is slow (over weeks to months)

WBRT after surgery or radiosurgery

Approximately 80% of patients of brain metastasis will eventually have multiple metastases

A phase III trial showed a relapse rate of 18% in the WBRT group vs 70% in the surgery-only group; p < 0.001

The following study showed no overt benefit and may increase neurotoxicity

Only recommend in more than one metastasis

JAMA 280(17), 1485–1489 (1998).

Chemotherapy

No standard paradigm for the use of chemotherapy for brain metastases

Temozolomide as an alkylating agent shows good BBB penetration, and has a favorable side-effect profile

Target therapy

Bevacizumab may be benefit

Be aware of intracranial hemorrhage

N. Engl. J. Med. 350(23), 2335–2342 (2004).Digestive and Liver Disease 43 (2011) 286–294

Prophylaxis of Brain Metastasis

prophylactic cranial irradiation: useful in SCLC and NSCLC with brain Mets 25 Gy in ten fractions to first-line treatment

responders In other cancers and neurotoxicity

need further validation VEGF-A inhibition(Experimental)

Bevacizumab

N. Engl. J. Med. 357(7), 664–672 (2007).

N. Engl. J. Med. 341(7), 476–484 (1999).Oncology 76(3), 220–228 (2009).

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