“FDG PET/CT in Lung Cancer”

Homer A. Macapinlac, M.D.

USA Cancer statistics, 2015

CA: A Cancer Journal for Clinicians Volume 65, Issue 1, pages 5-29, 5 JAN 2015 DOI: 10.3322/caac.21254 http://onlinelibrary.wiley.com/doi/10.3322/caac.21254/full#caac21254-fig-0001

Lung Cancer

• TNM staging is important for management and prognosis.

• Chest CECT is used to assess the primary tumor, direct mediastinoscopy, and detect intra- and extrathoracic metastases.

• MRI used in evaluation of superior sulcus tumors. • FDG PET/CT is used to improve the detection of

nodal and extrathoracic metastases, assess response, prognosis and detect recurrence.

Pathology Lung Cancer

• Two histologic categories are NSCLC and SCLC. • NSCLC is subdivided into SCC,

adenocarcinoma, and large cell carcinoma. • Adenocarcinoma is the most common

histologic subtype and is classified as AIS, MIA, invasive adenocarcinoma and variants of invasive adenocarcinoma.

Multi Modality Therapy of NSCLC

• Surgery is the treatment of choice in localized NSCLC. • Postoperative, adjuvant chemotherapy. • Combination Chemotherapy in patients with distant

metastasis • EGFR TKI, ALK inhibitors in certain NSCLC patients. • SBRT/IMRT/proton RT with or w/o chemotherapy in

medically inoperable patients with (stage I/II). • Concurrent chemoradiotherapy can be used to treat

patients with advanced-stage disease.

NSCLC Stage, Treatment and 5 Year Survival

I T1-2N0 Surgery 60-70% II T1-2N1 C/Surgery 40-55% T3N0 IIIa T3N1 C/Surgery 25% T1-3N2 CRT/Surg 10-25% IIIb T1-4N3 CRT 10-20%

T4 effusion Chemo <10% IV M1 Supportive <5%

6TH EDITION TNM 7TH EDITION TNM N0STAGE∗ N1STAGE∗ N2STAGE∗ N3STAGE∗

T1 (≤3 cm) T1a (≤2 cm) IA IIA IIIA IIIB

T1b (>2-3 cm) IA IIA IIIA IIIB

T2 (>3 cm) T2a (>3-5 cm) IB IIA (IIB) IIIA IIIB

T2b (>5-7 cm) IIA (IB) IIB IIIA IIIB

T3 (>7 cm) IIB (IB) IIIA (IIB) IIIA IIIB

T3 invasion T3 IIB IIIA IIIA IIIB

T4 (same lobe nodules T3 IIB (IIIB) IIIA (IIIB) IIIA (IIIB) IIIB

T4 (extension) T4 IIIA (IIIB) IIIA (IIIB) IIIB IIIB

M1 (ipsilateral lung) T4 IIIA (IV) IIIA (IV) IIIB (IV) IIIB (IV)

T4 (pleural effusion) M1a IV (IIIB) IV (IIIB) IV (IIIB) IV (IIIB)

M1 (contralateral lung) M1a IV IV IV IV

M1 (distant) M1b IV IV IV IV

TNM staging

Changes in TNM staging

• T descriptor changes: – tumors greater than 7 cm are now reclassified as T3 (previously T2) – additional nodule(s) in the lung (primary lobe) are reclassified as T3

(previously T4) – additional nodule(s) in the ipsilateral lung (different lobe) are

reclassified as T4 (previously M1) – malignant pleural effusions and pleural nodules are reclassified as M1

(previously T4).

• N descriptors are unchanged. • M1 descriptor is subclassified into M1a (additional nodules in

the contralateral lung) and M1b (distant metastases).

NCCN Guidelines Summary FDG PET/CT 7.2015

• SPN>8mm solid / partly solid, or enlarging • NSCLC: Stage I-IV

– Direct biopsy for T (avoid necrotic area) – Guide biopsy for mediastinal staging and M disease – 35-64% change in planned RT field

• SCLC – 16-38% change in Mx alterations in planned RT – Guide biopsy to change stage (N or M disease)

http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

The tumor formerly known as “BAC”

• Adenocarcinoma in situ (<3 cm, solitary, pure lepidic growth; formerly BAC),

• minimally invasive adenocarcinoma (<3 cm with predominant lepidic growth and ≤5-mm invasion),

• invasive adenocarcinoma, and variants of invasive adenocarcinoma.

Semin Nucl Med. 2012 Jul;42(4):255-60.

T staging

• CE CT of the Chest/Abd. – Local extent, nodules

• PET/CT if no M on CT – Biopsy viable site – Tumor from atelectasis

• Limitations – Microscopic tumor – Respiratory Motion – MIA (minimally invasive

adenocarcinoma ) – AIS (adenoca in situ)

2

The New Staging System for Lung Cancer: Imaging and Clinical Implications. Greaves, Susan; MRCP, FRCR; Brown, Kathleen; Garon, Edward; Garon, Bonnie Journal of Thoracic Imaging. 26(2):119-131, May 2011.

T1a ≤2 cm

T1b >2–3 cm

T2a >3-5 cm

T2b >5-7cm

T3 >7cm

Size cut-off points at 2 cm, 5, cm, 7cm

T3

• Tumor more than 7 cm or one that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium;

• or tumor in the main bronchus less than 2 cm distal to the carina* but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe as the primary

T3

“additional tumor nodule”

T4

• Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina

• separate tumor nodule(s) in a different ipsilateral lobe to that of the primary

T4

Staging - Lymph Nodes

NX, NO

N1 - Metastasis in ipsilateral peribronchial or hilar node, intrapulmonary node by direct extension

N2 - Ipsilateral mediastinal and/or subcarinal

N3 - Contralateral mediastinal or hilar, ipsilateral or contralateral scalene or supraclavicular

N stage

• CT: 55%sens, 81%spec • PET: improve accuracy

– 80-90% sens, 85-95% spec

• Endoscopic staging: – EBUS/EUS, w/ FNA

• Limitations: – microscopic disease – Distinguish

inflammation

Eur J Cardiothorac Surg. 2014 Feb 26

49-year-old man with NSCLC being evaluated for surgical resection.

Biopsy was positive for nodal metastatic disease and the patient underwent neoadjuvant chemotherapy followed by concurrent chemoradiation.

M stage • Detects up to 24 % mets

– Direct biopsy

• Change in management – Surgery to multimodality

to palliative – Prevents futile surgery

(20%)

• Stage shift, better outcome prediction

Erasmus JJ, Macapinlac HA, Swisher SG. Cancer. 2007 Sep 26

NSCLC: Initial treatment strategy

• Before: CXR, CECT chest/abd, bone scan – Metastatic workup: CT brain, plain film, MR – Mediastinoscopy to stage the mediastinum

• Current: CECT chest/abdomen and PET/CT or PET/CECT – Metastatic workup: MR brain, spine (Sup Sulcus)

• Change: FDG PET/CT up front (N/M staging) – Replaced bone scan, MR, plain film – Med VS EUS/EBUS surgery VS CRT (Curative or palliative)

• Practice Change: – Avoid futile thoracotomies (20%) – cost saving – Change management, predict outcome

Impact of initial PET/CT staging in terms of clinical stage, management plan, and prognosis in 592 patients with non-small-cell lung cancer.

• Our study showed that initial PET/CT staging not

only impacted stage and the management plan but also had prognostic value.

• Initial PET/CT changed the stage in 28.7 % of patients, and had a medium/high impact on the management plan in 37.2 % of patients.

• A medium/high impact of initial PET/CT staging on the management plan was an independent poor prognostic factor for PFS and OS in patients with NSCLC.

Takeuchi, et.al. Eur J Nucl Med Mol Imaging. 2014 Jan 18.

Overview

• 33,000 new cases of SCLC in USA • Nearly all attributable to cigarette smoking • Incidence decreasing but increasing in women • More rapid doubling time, higher growth

fraction, earlier development of metastases – Only 1/3 present with disease confined to chest – Sensitive to chemotherapy and radiotherapy – Surgery rare (Stage I), Clinical trials appropriate

Clinical Manifestations

• Cough, Dyspnea • Large hilar mass, bulky mediastinal nodes

– Sometimes peripheral nodule w/o central nodes

• Symptoms of metastatic disease (pain/neuro) • Paraneoplastic syndromes

– Lambert-Eaton myasthenic syndrome (Ab Ca chn) – Encephalomyelitis, sensory neuropathy (anti-Hu) – Cushing’s (ACTH), Hyponatremia (vasopressin)

SCLC Staging

• TNM staging by IASLC* and AJCC**

• Limited Stage: T any, N any, M0 – except T3-4 due to multiple lung nodules that

cannot fit in a tolerable radiation field

• Extensive Stage: T any, N any, M1 a/b and – T3-4 due to multiple lung nodules

*Goldstraw P. J Thorac Oncol. 2007;2:706–714. **Staging Manual 7th edition (2010)

FDG PET/CT in SCLC

• PET/CT is superior to PET alone – Ann Oncol. 2007 Feb;18(2):338-45.

• PET/CT can improve staging accuracy* – J Natl Compr Canc Netw. 2009 Jun;7 Suppl 2:S1-26. – *NCCN Guidelines Version 1.2013 SCLC

• Prospective studies – Most sensitive, better than conventional imaging (X-ray,

CT, MR, bone scanning) for most metastatic sites* – Except for brain metastases (MR/CT) – (120 patients) Eur J Nucl Med Mol Imaging. 2004 Dec;31(12):1614-20

FDG PET/CT in SCLC

• Stage migration: upstaging LD to ED in 6-33% and down staging ED to LD in (3-14%) – Cancer Treatment Reviews. 2011 Aug;73(2):121-6.

• 16-38% change in management due to alterations in planned RT field. – Clin Lung Cancer. 2008 Jan;9(1):30-4. – Int J Radiat Oncol Biol Phys. 2010 Jun 1;77(2):329-36.

• Pathology for lesions which may result in uptstaging • Mediastinal staging (EBUS/TBNA) to confirm PET/CT

findings prior to resection.

FDG PET/CT in SCLC Prognosis

• OS was significantly shorter in high versus low mean SUVmax (76 patients) Clin Cancer Res. 2009 Apr 1;15(7):2426-32.

• Total lesion glycolysis (TLG) could be a better prognostic indicator than SUVmax, as reported for other cancers (25 patients) Ann Nucl Med. 2011 Jul;25(6):406-13

• metabolic tumor volume (MTV) SUV 2.5 and integrated SUV (iSUV), were significantly correlated with OS and PFS (98 patients) Lung Cancer. 2011 Sep;73(3):332-7

• Stage and WBMTV (SUV of 3) are independent prognostic factors for PFS and OS (106 patients) Eur J Nucl Med Mol Imaging. 2012 Jun;39(6):925-35.

63-year-old man with SCLC presented with hemoptysis PET/CT scan shows patient had limited disease (disease confined to the thorax), treatment was concurrent chemoradiation

SCLC Pre-chemo SCLC Post-chemo

Predicting Response to Therapy

SCLC 5 year relative survival rate

Stage 5 year relative survival rate

I 31% II 19% III 8% IV 2%

FDG PET and PET/CT in SCLC Summary

• PET increases staging accuracy. • PET/CT is superior to PET alone. • 13% are upstaged and 4% down staged. • For most metastatic sites, PET/CT is superior. • PET/CT is inferior to MRI and CT for brain metastases • 16-38% change in management due to alterations in

planned RT field. • Pathology for lesions which may result in up-staging

Monitoring Response • Monitoring response is important in patients who

receive chemotherapy and/or RT. • Morphologic alterations detected by CT may not

correlate with pathologic response and tumor viability. • FDG-PET may allow an early and sensitive assessment

of the effectiveness of anticancer chemotherapy. • A decrease in FDG uptake before and after one cycle of

chemotherapy may predict outcome. • FDG-PET may be useful in determining response

patients with locally advanced but potentially resectable NSCLC who have completed neoadjuvant therapy.

NSCLC stage Study Year No. of patients Criteria for response on PET

Outcome measure

Design Hazard ratio* P

IIIA Vansteenkiste et al. (51)

1998 15 50% decrease in SUV

Overall survival Prospective NR 0.03

I–III MacManus et al. (21)

2003 73 CMR Overall survival Prospective 0.24 0.0004

IIIB–IV Weber et al. (56) 2003 57 20% decrease in SUV

Overall survival Prospective NR 0.005

IIB–III Hellwig et al. (47) 2004 47 SUV < 4 Overall survival Prospective NR <0.001

IIIA Hoekstra et al. (57)

2005 47 MRglu < 0.13 µmol/mL/min

Overall survival Prospective 0.33 0.0003

III Pottgen et al. (38)

2006 50 50% decrease in SUV

Time to extracerebral progression

Retrospective NR <0.005

III Eschmann et al. (53)

2007 70 CMR or 80% decrease in SUV

Overall survival Prospective NR 0.005

IB–IV de Geus-Oei et al. (55)

2007 51 MRglu > 47% Overall survival Prospective NR 0.017

35% decrease in SUV

0.018

IIIB–IV Nahmias et al. (40)

2007 16 Decrease in SUV at wk 1–3

Overall survival Prospective NR 0.0016

IIIA Dooms et al. (48) 2008 30 Pathologic response in MLN and >60% decrease in SUV in primary tumor

Overall survival Retrospective NR 0.002

IIIA–IIIB Decoster et al. (58)

2008 31 CMR Overall survival Retrospective NR 0.004

IB–IIIB

Tanvetyanon et al. (59)

2008

89

CMR or PMR

Overall survival

Prospective

NR

NS

Detection of Recurrence

• FDG-PET can be useful in detecting local recurrence of tumor after definitive treatment with surgery, chemotherapy, or RT before conventional imaging.

• Post 3D CRT/IMRT/Proton RT is particularly likely to manifest as opacities on CT that can be difficult to differentiate from tumor recurrence and the radiation-induced inflammatory changes can result in false-positive uptake of FDG.

Detection of recurrence

74-year-old woman with history of left upper lobe NSCLC 1 year after resection and chemoradiation therapy. PET/CT scan shows focal increased FDG uptake in radiation fibrosis. Malignancy was confirmed by transthoracic needle aspiration biopsy.

Recurrence of lung cancer

• Recurrent malignancy can be treated with repeat surgery, salvage chemotherapy, or RT.

• CT and MRI can be unreliable in distinguishing persistent or recurrent tumor from necrosis and posttreatment fibrosis.

• FDG-PET can detect local recurrence of tumor before conventional imaging.

• No standardized clinical algorithm has been developed to monitor patients with NSCLC for recurrence of disease after treatment.

Lung Cancer

• TNM staging is important for management and prognosis.

• Chest CECT is used to assess the primary tumor, direct mediastinoscopy, and detect intra- and extrathoracic metastases.

• MRI used in evaluation of superior sulcus tumors. • FDG PET/CT is used to improve the detection of

nodal and extrathoracic metastases, assess response, prognosis and detect recurrence.

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