PDT for Lung CancerCurrent status in clinical practice and 10 years in future

Harubumi Kato

Tokyo Medical University

International University of Health and Welfare

Niizashiki Central General Hospital

TMU, IUHW, NSCGH

First experience of patient with Cis

Cis was detected by sputum cytology (1978)

Spur of r-mid. & lower lobe br.Cis

TMU, IUHW, NSCGH

Worldwide increase of cancer patients

No improvement of death rate of cancer patients

Lung cancer patients Death

Europe 410,220 353,848

USA 214,226 167,545

Asia 1,045,695 936,051

Japan 94,855 75,119

(GLOBOCAN 2012)

TMU, IUHW, NSCGH

Eradication of Lung Cancer

Estimate 13,3500 in 2015 (Japan)

厚生労働省統計表データベース国民医療費

兆円

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00

0

5

10

15

20

25

30

35

1955 1960 1965 1970 1975 1980 1985 198919901991199219931994199519961997199819992000200120022003200420052006

National medical care expenses

Ratio of expenses per national income

Nat

ion

al m

edic

al c

are

exp

ense

s

Rat

io o

f ex

pen

ses

per

nat

ion

al i

nco

me

Annual trend of medical care expenses

-comparison to national income-

TMU, IUHW, NSCGH

4.1(25.4%)

5.9(28.8%)

8.9(33.1%)

11.2(37.2%)

11.7(37.5%)

11.7(37.9%)

11.7(36.9%)

11.6(36.1%)

11.6(35.1%)

11.3(34.0%)

11.3(33.0%)

16.0

20.6

27.0

30.131.1 31.0 31.5 32.1 33.1 33.1

34.1

6.1 5.9

7.2

8.18.6 8.7 8.8 8.8

9.1 8.9 9.1

0

1

2

3

4

5

6

7

8

9

10

0

5

10

15

20

25

30

35

40

1985 1990 1995 2000 2001 2002 2003 2004 2005 2006 2007

Nat

iona

l m

edic

al e

xpen

ses

com

pariso

n t

o n

atio

nal

inc

om

e

National medical expenses (trillion yen)

National medical expenses/National income

Elderly medical expenses (trillion yen)

(trillion JPY)

総務省統計局『国勢調査報告』および国立社会保障・人口問題研究所『日本の将来推計人口』（平成18年12月推計）

(%)

Annual trend of medical care expenses

TMU, IUHW, NSCGH

National medical care expenses 35.3 trillion yen

More than 70-year old 15.5 trillion yen

Per person

Less than 70 yo 160 thousand yen

More than 70 yo 776 thousand yen

More than 75 yo 882 thousand yen

August 26, 2010 MHLW

Medical Care Expenses of Elderly in 2009

TMU, IUHW, NSCGH

Central type lung cancer

1. Curative treatment

Early stage primary squamous cell carcinoma

Single, Multiple

2. Palliative treatment

Advanced central type squamous cell carcinoma

Neo-adjuvant treatment for surgery

Combination with chemotheray and/or radiotherapy

QOL

TMU, IUHW, NSCGH

PDT, Current Status in Clinical Practice

TMU, IUHW, NSCGH

What is Early Stage Lung Cancer (ESLC)?

Since 1975

Clinically curative lung cancer

Pathologically no invasive to vessels, lymph node and no metastasis

Location

Peripheral lung

Subsegmental bronchus - terminal alveolar bronchi

Less than 2cm

Central bronchus

Trachea – segmental bronchi

Endoscopically early stage squamous carcinoma

(1995, Japan Lung Cancer Society set a standard criteria)

WHO, UICC Staging: Stage 0, Tis

TMU, IUHW, NSCGH

What is ESLC treated curatively by PDT?

X-ray negative

CT negative

Central type squamous cell carcinoma

WHO,UICC & IASLC Staging: Stage 0, Tis

Endoscopic criteria (Japan Lung Cancer Society, 1995)

1 Bronchoscopically invisible type

2 Thickening type

3 Nodular type

4 Polypoid type

5 Mixed type

TMU, IUHW, NSCGH

Importance of Early Detection

Lung cancer screening program

Health check examination

For Central type

Sputum cytology

Symptoms: sputum, bloody sputum

Bronchoscopy

Symptoms: cough, bloody sputum

For Peripheral type

CT

TMU, IUHW, NSCGH

Lung Cancer, Japan

1960-1980 Smoker rate 75% in men, 15% in women

1960-1980 Serious air pollution

1980- Improvement of air pollution

1990’s- Decrease of smoker rate: 60%(1990) →32% (2013)

2000- Squamous ca decreased, Adenoca increased

1960-1980 Squamous cell ca 40%, Adenoca 35%

1999-2003 Squamous cell ca 30%, Adenoca 48%

家城隆次郎，他 過去3年間の肺癌における組織型の推移Toyoda Y, et al: Trends in lung cancer incidence by histology in Osaka Jpn J Clin Oncol 2008

TMU, IUHW, NSCGH

Who are indicated for PDT?

High risk people to lung cancer

Heavy smoker

High risk occupations

COPD

Emphysema

Symptom

Bloody sputum

Sputum

Cough

Multiple lung cancer patient

Post operative patients

TMU, IUHW, NSCGH

PDT for Lung cancer (ESLC)

1997~ 2002~

Photofrin 2mg/kg iv Laserphyrin 1mg/kg iv

48 hours prior to PDT 4 hours prior to PDT

PDT with 150 J/cm2 PDT with 100 J/cm2

Excimer/Argon Dye Laser Diode Laser

Shading for 30 days Shading for 5 days

TMU, IUHW, NSCGH

PDT for ESLC

Lt B1+2, 3 (Sq.ca.) 79-year old man

Before PDT 3M after PDT

TMU, IUHW, NSCGH

PDT for ESLC

Before PDT 3M after PDT

Lt. u. br. (Sq.ca.) 68-year old man

TMU, IUHW, NSCGH

PDT for ESLC

Before PDT 3M after PDT

Lt. u. br. (Sq.ca.) 68-year old man

63-year old man

PDD & PDT for ESLC

Carina (Sq. cell carcinoma)

Before PDT PDD 3 M after PDT

Photosensitizer: Laserphyrin + SAFE 3000

TMU, IUHW, NSCGH

Squamous cell carcinoma Rt. B1a-B1b spur 68y, Man

OCT for ESLC (Cis)

Cartilage

SAFE 3000 AF OCT

Pentax SOCT-1000

CisCis

Basement membrane

TMU, IUHW, NSCGH

TMU, IUHW, NSCGH

PDT for ESLC

Before PDT 3M after PDT

Carina (Sq.ca.) 79-year old man

R-upper brB2-3 bifurcation

PDD

PDD

AFD

PDT

AFD

AFD AFD

AFD

PDT

PDTPDT

PDD

L-upper br

Orifice of upper lob

Upper division

Bifurcation of upper div. & B4.5

63-year old man

heavy smoker (Sq. ca.)

12 sessions of PDT

sincee 2010

TMU, IUHW, NSCGH

PDD & PDT for Multiple ESLC

TMU, IUHW, NSCGH

Results of PDT for ESLC

Furuse et al Kato et al Usuda et al

No. 59 264 91

Photosensitizer Photofrin Photofrin(Laserphyin in 16) Laserphyrin

Size (cm) & CR (rate,%)

≦ 1.0 97.8% 93.9% 94.0%

1.0-2.0 50.0% 80.0% 90.4%

2.0< 37.5% 44.1% ---

Ikeda,N,etal Laser in Surg and Med 43:749-754, 2011

Photofrin ® vs Laserphyrin ®

Absorption spectrum and structure of Laserphyrin

N HN

NNH

H3C

H3CH

CH2

CO2NaNaO2C

CH3H3C

NaO2C

H

CO2Na

HCH3

HN

O

Wavelength

Ab

sorb

an

ce

300 400 500 600 700

Photofrin

Talaporfin (Laserphyrin)

Hemoglobin

630nm

664nm

(NPe6)

TMUH & NSCGH

Clinical Use of Photosensitizers

Photofrin (Axcan)*1: Lung ca, Esophageal cancer (Jap, USA, Eur)

Gastric ca, Cervical ca & dysplasia (Jap)

Bladder ca (Can)

Barrett disease (USA, Eur)

Foscan (Biolitec)*2 Head & neck cancer (Eur)

Levulan (DUSA)*3 Keratosis (Can, Latin Am, Kor)

Condyloma (Chin)

Metvix (Photocure)*4 Basal cell cancer (Eur)

Keratosis (USA, Eur, Austr)

Hexvix (Photocure)*5 Bladder cancer (Scand)

MRSAid (Ondine Biomedical) Infection (Can)

ALA (Biofrontera)*6 Keratosis (Ger)

Laserphyrin (Meiji)*7 Lung ca (Jap)

Visudyne (Novartis)*8 AMD (Jap, USA, Eur)

Myopia, Ocular histoplasmosis (USA, Eur)

*1Porfimer sodium,*2Temoporfin,*3Aminolevulic acid,*4Methyl-aminolevulinate,*5Hexaminolevulinate

*65-aminolevulic acid(nanocolloidal),*7Talaporfin sodium,*8Verteporfin

TMUH & NSCGH

5-year survival rate, PDT in ESLC

57.6%

92.5%

0 20 30 40 50 6010

Time (month)

20

0

100

80

60

40Su

rviv

al

rati

o (

%)

Cancer specific survival

Overall survival

57.6%

92.5%

0 20 30 40 50 6010

Time (month)

20

0

100

80

60

40Su

rviv

al

rati

o (

%)

57.6%57.6%

92.5%92.5%

0 20 30 40 50 6010

20

0

100

80

60

40Su

rviv

al

rati

o (

%)

0 20 30 40 50 60100 20 30 40 50 60100 20 30 40 50 6010

20

0

100

80

60

40Su

rviv

al

rati

o (

%)

20

0

100

80

60

40

20

0

100

80

60

40Su

rviv

al

rati

o (

%)

Cancer specific survival

Overall survival

Cancer specific survivalCancer specific survival

Overall survivalOverall survival

TMU, IUHW, NSCGH

Current Status of PDT for Advanced Lung Cancer

1. Palliative treatment for the improvement of QOL

Obstructive pneumonia or atelectasis

2. Chemo/radiotherapy + PDT

+ Immunological response

3. Neoadjuvant PDT for surgery

Possibility of extended surgery after PDT

Possibility of reduction surgery after PDT

TMU, IUHW, NSCGH

Indication Criteria for Advanced Lung Ca

Inclusion1. Dyspnea due to stenosis or obstruction of central bronchus

2. Obstructive pneumonia or atelectasis

3. Possibility of extended surgery after PDT

4. Possibility of reduction of resection volume after PDT

5. Recurrence after radio/chemotherapy

6. Maintenance of QOL in combination with radio/chemotherapy

7. ECOG Performance Status 0-II

8. Adequate organ function

9. Life expectancy at least 12 weeks

10. Written informed consent

Exclusion1. Serious complications

TMU, IUHW, NSCGH

PDT for QOL, Advanced Lung Cancer

TMU, IUHW, NSCGH

Improvement of Patients Condition

PaO2

(AV+SD)mmHg66 ± 21 82 ± 14

PS 1.8 ± 0.5 0.8 ± 0.4

Before PDT After PDT

TMU, IUHW, NSCGH

PDT

77y man, heavy smoker

l-upper division, Sq ca

PDT+Chemo(CBDCA+TS-1)

TMU, IUHW, NSCGH

Early stage lung squamous cell carcinoma

CR 93.8-78% (1982-2004, Kato H, Cortese D, Monnier P , Furuse K)

Advanced lung squamous cell carcinoma

1.For QOL (Opening of obstructive bronchus)

PR 100-55% (1982-1999, Kato H, Vincent, Balchum O, McCaughan,

LoCicero, SutedjaT, Wieman, Moghissi)

2.Neo-adjuvant PDT for the surgery

Kato H (J Cardiovasc Surg,1985),

Okunaka T (Diag Thera Endoscopy,1999)

3.Combination therapy with chemotherapy and or radiotherapy

Miyajima K, in press

References of PDT for Lung Cancer

TMU, IUHW, NSCGH

Combination therapy with chemo+radiotherapy

TMU, IUHW, NSCGH

age histology c-stage Chemo KL-6(<500) location rad

1 77 Sq IIA CBDCA+TS-1 226 L-B1+2 +

2 74 LCNEC IIIB NDP+DOC 647 R-intermedius +

3 74 Sq IIBCBDCA+TS-1

CBDCA+VNR655

R Intermedius+

4 69 Ad IV TS-1 530 R-main broncus +

5 75 Sq IV CDDP+DOC 192 R-main bronchus +

6 74 Giant IV CDDP+DOC 846 Basal +

7 72 Sq IV CDDP+DOC 454 Carina +

8 58 Sq IIIB CBDCA+TS-1 175 R-B2,3 +

9 77 Sq IIIA NDP+DOC 647 R-upper bronchus +

10 78 ad IIIACBDCA+PEM+Bev

CBDCA+PTX+Bev960 R-B3 ＋

11 80 ad IV CBDCA+PEM+Bev 453 R-upper bronchus ＋

1. Palliative treatment for the improvement of QOL

2. Neoadjuvant PDT for surgery

PDT for advanced lung cancer

TMU, IUHW, NSCGH

Bronchoplasty after preoperative PDT

78y man, Sq.Ca., Stage IIA (T1 N1 M0)

TMU, IUHW, NSCGH

Bronchoplasty by Preoperative PDT

Resection of bifurcation between the left upper and lower bronchi

Before PDT After PDT After resection

TMU, IUHW, NSCGH

PDT plus Bronchoplasty for ESLC

Kato H. et al.

1985

J Thorac

Cardiovasc

Surg 90:420

-429

15 patients received preoperative PDT for the purpose of

either reducing the extent of resection or increasing operability.

Operation was performed 1 to 9 weeks after PDT

5 patients of stage I, originally candidates for pneumonectomy

or bilobectomy, became possible to sleevelobectomy

Okunaka T,

Kato H

1999

Dig Thera

End 5:155

-160

26 lung cancer patients received the preoparative PDT.

The initial purpose of PDT to reduce extent of resection was

achieved 22 out of 26.

7 patients, stage I, tumor invasion to the main bronchus or trunks

intermedius became possible to sleevelobectomy

TMU, IUHW, NSCGH

Future direction of PDT for Lung Cancer

Significant increase of lung cancer throughout world!

Curative PDT for the early stage lung cancer

Central type squamous cell carcinoma

Peripheral type adenocarcinoma

TMU, IUHW, NSCGH

Computor navigation

TMU, IUHW, NSCGH

Bronchus LungPoint Ⓡ

TMU, IUHW, NSCGH

Bronchus Medical, Inc.

Adenocarcinoma in situ (BAC)

1.5cm

Noguchi Type A

pT1N0M0

StageⅠA

GGO

TMU, IUHW, NSCGH

normal BAC (mucinous)

Thickening of alveolar wall

Dilatation of alveoli

Increase of interstitial tissue

(Pentax SOCT-2000)

Possibility of definitive diagnosis by OCT

TMU, IUHW, NSCGH

Lung cancer treatments

Worldwide increase of cancer patients

No improvement of death rate of cancer patients

Increase of medical cost of cancer patients

Cancer patients demand:

High quality treatments

Safe treatments

No invasive treatments

Low cost treatments

TMU, IUHW, NSCGH

H.Kato et al: Analysis of the Cost-effectiveness of PDT in Early Stage Lung Cancer.

Diagnostic and Therapeutic Endoscopy; 6,9-16,1999

Medical expenses of PDT vs Surgery

PDT 760,000yen ($ 8,444)

DPC 249, 430yen ($ 2,772)

PDT procedure 87,100 ( 967)

Laserphyrin 387,200 ( 4,302)

Bronchoscopy 25,000 ( 277)

Surgery 1,700,000yen ($ 18,888)

DPC 274,200yen ($ 3,046)

Surgical procedure 1,050,000 ( 11,666)

Anesthesia, drugs 300,000 ( 3,333)

TMU, IUHW, NSCGH

H.Kato et al: Analysis of the Cost-effectiveness of PDT in Early Stage Lung Cancer.

Diagnostic and Therapeutic Endoscopy; 6,9-16,1999

Photosensitizers, future

Infrared range photosensitizers

Texaphyrin, Benzopophyrin derivatives

Compound metalic photosensitizers

Tungsten, Gold (Au-NPe6) for X-ray and Synchrotron

Micelle, Nano-particle compound photosensitizer

Phthalocyanine-nanoparticle (albumin, liposome etc)

Targeted photosensitizers

Molecular targeted photosensitizer

Targeting via ligand-receptor interlaction

(Cancer cell recepter)

Small molecular

Antibody-conjugate (EGFR, HER2, Tumor-vessel

specific fibronectin variant (EDB domain

TMU, IUHW, NSCGH

Lights, future

LED

Long wavelength laser

X-ray

Synchrotron radiation

X-ray laser

TMU, IUHW, NSCGH

Japan Society of Lung Cancer, Japanese Photodynamic Association, Japan Society of Laser Surgery and Medicin

Diagnosis of early stage lung cancer

Pathological T1A, Tcis

Endoscopical early-stage lung cancer

Normal chest X-ray and CT imaging

No evidence of metastasis to lymph nodes

Superficial tumor not more than 2.0 cm in diameter

Obvious peripheral margin of the tumor

Guideline of PDT for ESLC

TMU, IUHW, NSCGH

Toward Lung Cancer Eradication

Smoking cessation & clean air

Early detection

Early localization

Early treatment by PDTTMU, IUHW, NSCGH

Development Toward Ideal Therapy

TMU, IUHW, NSCGH

Early detection

High quality treatments

Safe treatments

No invasive treatments

Low cost treatments

謝 謝

TMU, IUHW, NSCGH