Kshivets O. Lung Cancer Surgery

5-Year Survival of Non-Small Cell Lung Cancer Patients after Adjuvant

Chemoimmunoradiotherapy

Oleg Kshivets, M.D., Ph.D.Department of Surgery, Siauliai Public Hospital, Lithuania

The 53rd Annual Cancer Symposium of Society of Surgical OncologyNew Orleans, The USA, 2000

Abstract: FIVE-YEAR SURVIVAL AND LIFE SPAN OF NON-SMALL CELL LUNG CANCER PATIENTS AFTER ADJUVANT CHEMOIMMUNORADIOTHERAPY O.Kshivets* Siauliai Cancer Center, Siauliai, Lithuania Purpose: This study aimed to determine expediency of adjuvant chemoimmunoradiotherapy (AT) for radical operated non-

small cell lung cancer (C) patients (LCP) with pathologic stage II-III (T1-4N0-2M0G1-3). Methods: In randomised trial (1985-1998) 5-year survival (5YS) of 54 radical operated LCP after AT (age=54.41.0 years;

males=49, females=5; C size=4.70.2 cm) was compared with 5YS of 264 LCP after radical procedures (S) (age=55.80.5 years; males=240, females=24; C size=4.50.1 cm) and with 5YS of 86 radical operated LCP after postoperative radiation (R) (45-50 Gy) (age=58.00.8 years; males=74, females=12; C size=4.70.2 cm). Variables selected for 5YS study were sex, age, TNMG, cell type, C size. 1 cycle of chemoimmunotherapy (CAVT: cyclophosphamid 500 mg/m2 IV+doxorubicin 50 mg/m2 IV+vincristin 1.4 mg/m2 IV on day 1; thymalin/taktivin 20 mg IM daily for 5 days) was given on 10-14 day after S. R (45-50 Gy) was administered since 7 day after 1 cycle. After R 3-4 courses of CAVT were repeated every 21-28 day. Representativeness of samplings was reached by means of randomisation based on unrepeated random selection. Multiple correspondence analysis (A), cluster A, confirmatory factor A, structural equation modeling, Monte Carlo simulation were used to determine any significant overall differences between survival of LCP after AT, S, R.

Results: 5YS was superior in AT group (64.8%: 35 from 54 LCP with N0-2; life span: LS=1998.2156.9 days) compared with R group (45.3%: 39 from 86 LCP with N0-2; LS=1296.4109.5 days) (P<0.001). 5YS of S group was 63.6% (168 from 264 LCP with N0-2; LS=1738.363.4 days) (P>0.05 for AT and P<0.001 for R). For LCP with N1-2 5YS was significantly superior for AT group (63.6%: 21 from 33; LS=1934.0189.9 days) compared with S group (28.1%: 25 from 89; LS=1056.991.1 days) (P<0.001) and with R group (35.6%: 21 from 59; LS=1051.7119.6 days) (P<0.001). Rates of age, sex, T1-4, G1-3, cell type, C size for LCP after AT, S and R were not significantly different. Structural equation modeling and Monte Carlo simulation confirmed significant overall differences between 5YS (P<0.05) and LS (P<0.001) of LCP with N1-2 after AT with respect to S or R; however, 5YS of LCP for N0 with or without AT and R were not significantly different.

Samplings:

Lung Cancer Patients Lived More than 5 Years after Complete Resections..…...242

Lung Cancer Patients Died Because Generalization During First 5 Years after Complete Resections.…….…………...162

In All…………………………………...404

Samplings:

Adjuvant Chemoimmunoradiotherapy…………..54

Postoperative Radiotherapy..……...…..86 Surgery Alone…………………………264 In All…………………………………...404

Radical Procedures:

Pneumonectomy…………………..175 Upper/Lower Bilobectomy…………21 Upper Lobectomy…………………136 Lower Lobectomy………………….66 Middle Lobectomy………………….6 Combined Procedures……………..49 In All…………………………...….404

Staging:

T1…..118 N0..…223 G1…..100 T2…..187 N1……97 G2…..104 T3……84 N2……84 G3…..200 T4……15 Stage II...111 Stage III...293 Squamous Cell Carcinoma…..……….263 Adenocarcinoma………………………116 Large Cell Carcinoma………………….25

5-Year Survivors and Losts Bivariate Histogram: 5-Year Survival and Treatment

Lung Cancer Patients with N0, n=223Bivariate Histogram: 5-Year Survival and Treatment

Lung Cancer Patients with N1-2, n=181

Bivariate Histogram: 5-Year Survivor and Treatment Lung Cancer Patients with N0-2, n=404

Results of Factor AnalysisResults of Factor Analysis, Factor Loadings, Factor 1 vs. Factor 2

Rotation: Varimax normalizedExtraction: Principal components


Factor 1

Fact

or 2

Age

WeightGender

5-Year SurvivalLife SpanT

N

G Stage

Tumor Size

Histology

Procedures

Radiation

Surgery

CHT+IT+R

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

-0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0

Results of Factor Analysis, Factor Loadings, Factor 1 vs. Factor 2Rotation: Varimax normalized

Extraction: Principal componentsLung Cancer Patients with N1-2, n=181

Factor 1

Fact

or 2 Age

Weight

Gender

5-Year Survival

Life Span

TN

GStageD Histology

Procedures

Radiation Surgery

CHT+IT+R

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

-0.3 -0.1 0.1 0.3 0.5 0.7 0.9

Results of Factor Analysis

1.266 1.359 1.452 1.546 1.639 1.733 1.826 1.920 2.013 2.107 above

Quadratic SurfaceCHt+IT+r vs. SURGERY vs. 5-Year Survival


1.063 1.144 1.224 1.305 1.386 1.466 1.547 1.627 1.708 1.789 above

Quadratic SurfaceCHT+IT+R vs. RADIATION vs.5-Year Survival


1.244 1.289 1.335 1.380 1.425 1.470 1.515 1.561 1.606 1.651 above

Quadratic SurfaceCHT+IT+R vs. SURGERY vs. 5-Year Survival


1.276 1.325 1.374 1.423 1.472 1.521 1.570 1.620 1.669 1.718 above

Quadratic SurfaceCHT+IT+R vs. RADIATION vs. 5-Year Survival


Nucloids of Lung Cancer Patients with N0-2, n=404

Results of Cluster-Analysis of Clinicopathologic

Characteristics of Lung Cancer Patients with N0-2, n=404

Nucloids of Lung Cancer Patients with N1-2, n=181

Results of Cluster-Analysis of Clinicopathologic Characteristics of Lung Cancer Patients with N1-2, n=181

Network-Model of Lung Cancer Patients with

N0-2 (n=404)

Network-Model of Lung Cancer Patients with N0 (n=223)

Network-Model of Lung Cancer Patients with N1-2 (n=181)

Survival of Lung Cancer Patients with N0-2 (n=404)

Cumulative Proportion Surviving (Kaplan-Meier)Complete Censored

Lung Cancer Patients, n=404 (N0-N1-N2)Global Chi2=14.34; Df=2; P=0.00077

Time (months) after complete resections

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180 200

Only Complete Resections, n=264Postoperative Radiotherapy, n=86Adjuvant Chemoimmunoradiotherapy, n=54

Proportional Hazard (Cox) Regression Model of Lung Cancer Patients with N0-2, n=404

Survival Function for Mean Values of Independent VariablesProportional Hazard (Cox) Regression

Lung Cancer Patients, n=404 (N0-N1-N2)Chi2=129.33; Df=13; P=0.000000

Survival Time (Months)

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

1.05

0 20 40 60 80 100 120 140 160 180 200

Logistic Regression Model of Lung Cancer Patients with N0-2, n=404

ExpectedNormal

Frequency Distribution: ResidualsLung Cancer Patients with N0-2, n=404

Logistic Regression ModelsChi2=109.27; Df=13; P=0.0000000

No

of o

bs

0102030405060708090

100110120

-1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2


Normal Probability Plot of ResidualsLung Cancer Patients with N0-2, n=404

Logistic Regression ModelChi2=109.27; Df=13; P=0.0000000

Residuals

Expe

cted

Nor

mal

Val

ue

-3.5

-2.5

-1.5

-0.5

0.5

1.5

2.5

3.5

-1.2 -0.8 -0.4 0.0 0.4 0.8 1.2

SEPATH-Model: Clinicopathologic Characteristics-Survival of Lung Cancer Patients with N0-2 metastases

(n=404)Normal Probability Plot, Normalized Residuals

Lung Cancer Patients with N0-N2 (n=404), Global Chi2=378.69; Df 63; P=0.000000SEPATH-model: Anthropometry-Cancer-Surgery-Radiotherapy-

Ad.Chemoimmunoradiotherapy-Survival (5-year Survival, Life Span)Surgery P=0.276; Ad.CHIRT P=0.558; Ad.Radiation P=0.005;

Value

Expe

cted

Nor

mal

Val

ue

-3

-2

-1

0

1

2

3

-10 -8 -6 -4 -2 0 2 4 6



Lung Cancer Patients, n=404 (N0-N1-N2)Global Chi2=92.32; Df=2; P=0.000000000

Time (munths) after complete resections

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180 200

N0, n=223N1, n=97N2, n=84



Lung Cancer Patients, n=181 (N1-N2)Global Chi2=11.951; Df=2; P=0.00254

Time (monts) after complete resections

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160

Only comlete Resections, n=89Posoperative Radiotherapy, n=59Adjuvant Chemoimmunoradiotherapy, n=33

Proportional Hazard (Cox) Regression Model of

Lung Cancer Patients with N1-2, n=181 Survival Function for Mean Values of Independent Variables

Proportional Hazard (Cox) RegressionLung Cancer Patients, n=181 (N1-N2)

Chi2=53.01; Df=13; P=0.00000

Survival Time (Months)

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160


ExpectedNormal

Frequency Distribution: ResidualsLung Cancer Patients with N1-2, n=181


No

of o

bs

0

5

10

15

20

25

30

35

40

45

50

-1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2


Normal Probability Plot of ResidualsLung Cancer Patients with N1-2, n=181


Residuals

Expe

cted

Nor

mal

Val

ue

-3.5

-2.5

-1.5

-0.5

0.5

1.5

2.5

3.5

-1.0 -0.6 -0.2 0.2 0.6 1.0

SEPATH-Model: Clinicopathologic Characteristics-Survival of Lung Cancer Patients with N1-2 metastases

(n=181) Normal Probability Plot, Normalized Residuals

Lung Cancer Patients with N1-2 (n=181), Global Chi2=193.45; Df=63; P=0.000000 SEPATH-Model: Anthropometry-Cancer-Surgery-Radiotherapy-

Ad.Chemoimmunoradiotherapy-Survival (5-year Survival, Life Span) Surgery P=0.905; Ad.CHIRT P=0.0000001; Ad.Radiation P=0.909;

Value

Expe

cted

Nor

mal

Val

ue

-3

-2

-1

0

1

2

3

-6 -4 -2 0 2 4 6 8

Results of Monte Carlo Simulation

-0.475 -0.055 0.364 0.783 1.203 1.622 2.041 2.460 2.880 3.299 above

Monte Carlo Data SimulationLung Cancer Patients with N0-2, n=404

-0.475 -0.055 0.364 0.783 1.203 1.622 2.041 2.460 2.880 3.299 above


-0.475 -0.055 0.364 0.783 1.203 1.622 2.041 2.460 2.880 3.299 above


-0.475 -0.055 0.364 0.783 1.203 1.622 2.041 2.460 2.880 3.299 above


Life Span of Died Lung Cancer Patients with N0-2 (n=162)


Died Lung Cancer Patients with N0-2 (n=162)Global Chi2=6.612; Df=2; P=0.037

Time (Months) after Complete Resections

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

-0.10.00.10.20.30.40.50.60.70.80.91.0

0 10 20 30 40 50 60 70

Surgery alone, n=96Postoperative Radiotherapy, n=47Adjuvant Chemoimmunoradiotherapy, n=19

Conclusions: Adjuvant chemoimmunoradiotherapy significantly

improved 5-year survival and life span of non-small cell lung cancer patients with N1-2 metastases after complete resections compared with surgery alone and postoperative radiotherapy.

One must be careful in using adjuvant chemoimmunoradiotherapy for lung cancer patients without lymph node metastases.

Address: Oleg Kshivets, M.D., Ph.D. Consultant Thoracic/Abdominal Surgeon Department of Surgery Siauliai Public Hospital Tilzes:42-16, LT78206, Siauliai, Lithuania tel (37041)416614 e-mail: [email protected]

Kshivets O. Lung Cancer Surgery

Health & Medicine

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