ancer hemotherapy and harmacology

Cancer Chemother. Pharmacol. 1, 145-159 (1978)

© Springer-Verlag 1978

Chemotherapy as an Adjuvant to Surgery in Lung Cancer* K. Karrer 1, N. Pridun 2, and H. Denck 3 l Department of Epidemiology, Institute for Cancer Research, University of Vienna, Borschkegasse 8a, A-1090 Wien, Austria 2 I. Surgical Department of the Hospital of Vienna-Lainz, Wien, Austria 3 Ludwig-BoltzmannInstitute for Clinical Ontology, Vierma-Lainz, Wien, Austria

Summary. A preliminary evaluation of an adjuvant chemotherapy is presented. A highly dosed intermittent polychemotherapy consisting of 13 courses of three infusions separated by intervals of a week was administered over 3 years. Each infusion contained 12 mg/kg cyclophosphamide, 12 mg/kg 5-fluorouracil (5-FU), 0.5 mg/kg methotrexate and 0.1 mg/kg vinblastine. In all, 2,442 such infusions were given to 219patients who had undergone radical surgery for bronchial carcinomas. This treatment was generally well tolerated; the leucopenia rate was within an acceptable range. A randomized control group consisting of 289 patients treated by radical surgery only was checked and examined at the same intervals as 229 patients who were allocated to the adjuvant chemotherapy group. Comparison of the survival rates of the subdivided treatment groups and control groups, calculated by the lifetable method, shows differences in the prognosis, as well as in the effectiveness of the one chemotherapy used. These differences also existed with regard to tumor size (according to TNM stages), to the clinical symptoms (according to the Feinstein classification), and to the histological main tumor types. In the first years after onset of treatment in the groups of patients who had tumors of TNM stages I and 11, a difference appears in the life-table curves favoring the chemotherapy-treated patients. In TNM stages III, IV, and C there seems to be an increase in survival rates. One hypothesis is that the chemotherapy had a greater effect on the more rapidly growing tumors than seems to be the case in the slower-growing tumors. Squamous-cell and adenocarcinomas seem to be unfavorably influenced by this therapy, while a positive therapeutic effect seems observable in the carcinomas of the small-cell and of the other different histological types. * This study was supported by the Paul-Ehrlich Society for Chemotherapy Reprint requests should be addressed to: Karl Karrer

Of the more rapidly growing tumors (Feinstein 3 and 5, subdivided into squamous, adeno- and other cell type tumors) on the other hand, a therapeutic effectiveness of the chemotherapy in squamous-celI tumors too seems apparent. The necessity of close cooperation with the family physicians is emphasized. The observable differences of the treatment efficacy in patients with various biologically different tumor types, as seen in this preliminary evaluation, permit the formulation of working hypotheses which could lead to treatment optima for the various tumor types. Taking into account the length of time necessary to conduct such a trial and to reach meaningful results, it is evident that with the increasing number of treatment possibilities such working hypotheses must be tested within the framework of larger international cooperative study groups.

Introduction

From the results of previous studies it has been coneluded that adjuvant chemotherapy should be administered intermittently at the highest possible doses over a long period of time (Karrer and Denck, 1971). As results of chemotherapy in patients with inoperable carcinomas of the bronchus indicate, a combination of cytostatics with different modes of action is superior to mono-drug therapy. The application of a combination of cytostatic drugs after radical surgery seems to be the best treatment at present. This form of treatment, with long-term intermittent polychemotherapy seems to achieve a promising compromise between tumor inhibitory efficacy and undesirable effects such as immunosuppression. In order to attain a maximal destruction of small tumor foci in the whole body the highest possible dose,

0344-5704/78/0001/0145/$ 03.00

146

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

limited according to the resulting side effects, should be administered. Therefore, a randomized clinical trial was initiated to determine whether a high-dosed intermittent long-term polychemotherapy can increasing the survival rate and/or survival time of patients who have undergone radical surgery for bronchial carcinoma. The trial was begun in autumn 1969 by the cooperative Viennese working group.

Material and Methods The preoperative diagnostic procedures used to evaluate the anatomical size of the tumor are performed in the following sequence: Xray, bronchoscopy, and mediastinoscopy including histology and angiography. Internal medical contraindications for surgery are decided on the basis of examinations such as ECG and lung function tests, and other tests if indicated. All the patients in this study are operated on in this hospital by one group of surgeons from one surgical school using the same methods of operation and criteria of indication for surgery. No other selection of patients was performed in the hospital and no patients in this study have been operated on outside this hospital. All slides made of the operation specimens have been evaluated by the same pathologist. All patients are randomized after surgery. The stratification of the patients is performed thereafter according to the TNM classification based on histological examination of the operation specimens (Kreyberg et al., 1967), Feinstein classification (Feinstein, 1964), and histological main types. Thus four groups of patients are categorized: squamous-cell, adeno-, small-cell, and all other types of carcinomas, termed "diverse". No unknown histological type is included in this study. Radical surgery is defined as the removal of the whole primary tumor together with the surrounding involved tissue. This is performed by lobectomy, bilobectomy or pneumonectomy, according to the localization and size of the primary tumor. The regional lymph nodes are also removed by this procedure. Additional lymph nodes are also removed if macroscopieally involved. The operation specimen is examined by the same pathologist. The cutting board and the extent of the primary tumor as well as the labeled removed lymph nodes are evaluated. This provides the evidence for the subsequent postoperative TNM staging. After histological examination of each operation specimen, two groups of patients are formed at random: one group receives adjuvant chemotherapy and the second group receives none and is used as a control group. No X-ray treatment was used at this stage. Both groups of patients received the same general medical care at equal intervals. Chemotherapy was carried out as follows: 1-2 weeks after surgery the first intravenous infusion of 500 ml of 5% laevulose containing 12 mg/kg cyclophosphamide, 12 mg/kg 5-FU, 0.5 mg/kg methotrexate, and 0.1 mg/kg vinblastine was administered. This infusion was repeated a second and a third time at intervals of 7 days. The protocol requires the administration of 13 such series of three infusions within 3 years after surgery. The first series of three infusions is given within the usual time required for hospitalization for this type of operation. Subsequent infusions are given in the outpatient clinic. The hematogram is determined before chemotherapy is started. The minimum hematological level must be: 4,000,000 erythrocytes, 4,000 leucocytes, and 100,000 platelets per mm 3. During therapy a leucocyte count is required twice weekly. If the leucocyte and

platelet counts fall below 4,000 and 100,000/ram a respectively, the intervals without treatment are prolonged. The chemotherapy protocol was followed as closely as possible. No reduction schedule of chemotherapy was used. However, the interval of no treatment was prolonged as made necessary by low white blood counts. The exact number of chemotherapy infusions administered to the patients is given in Figures 1-5, in which each line represents one patient, giving the individual number of infusions and showing intervals and their lengths. The chemotherapy is given in the outpatient clinic of the hospital, where the blood counts are also performed. Patients from outside Vienna are also treated (i.e., chemotherapy administration) and examined in the outpatient clinic mentioned above. Monitoring examinations including X-rays, blood counts, body weight, etc. are performed every 6 weeks for the first 6 months, every 3 months for the next 18 months, and then every 6 months. Close cooperation with the referring family physician is important. Therefore, the general practitioner is informed by an explanatory letter and asked to provide psychological support, advice, and care of the patients. The private physician is only requested to treat the general physical condition of the patient, but no cytostatic chemotherapy is administered by him. As indicated in Figures 1 through 5, many of these patients (predominantly from outside Vienna) are not willing to undergo regular chemotherapy. This is often because the patient does not understand his diagnosis and prognosis, which one is usually not told in Austria. Therefore treatment is unfortunately not administered to all patients, as would be required according to the protocol. Because they are convinced neither of the necessity for the long-term therapy nor of the rationale of the adjuvant chemotherapy, not only the patients themselves but also some of the private physicians involved do not cooperate in supporting the maintenance of the protocol schedule. The preliminary evaluation of this study, at January 1, 1977, is based on 518 patients and is focused on the question of tolerance and survival. The parameter used for the evaluation of the chemotherapy administered is the survival time from the point of surgical tumor removal up to the patient's demise. Of the 518 patients, 289 received only surgical treatment (randomized controls) and 229 patients were treated both surgically and with chemotherapeutic agents. To define different prognostic groups of bronchogenic carcinomas and their reactions to the uniform therapy, detailed stratifications were used. This was accomplished by a definite description and classification of the tumor at the time of resection, using the TNM system (Arnal e t al., 1967), the Feinstein categories (Feinstein, 1964), and histological maintypes (Kreyberg et al., 1967). Calculation of the life-table survival curves is based on all randomized patients, including the postoperative mortality without exception even in the case of protocol violation or deviation. The establishment of criteria for defining whether or not treatment is adequate appears premature at the present stage of the investigation. The extent of disease is classified as follows: T1-

Tumor 3 cm or less in its greatest dimension, surrounded by lung or visceral pleura and with no evidence of invasion proximal to a lobar bronchus. Tumor limited at the lung segment of origin.

T2 -

Tumor more than 3 cm in its greatest dimension and not extending beyond the lung.

T 3 --

Tumor of any size with direct extension to adjacent structures such as the main bronchus, the chest wall, diaphragm, and mediastinum and its contents.

T4 -

Tumor extending far beyond the border of the lung, infiltrating the adjacent structures such as the pericard, chest wall, diaphragm, or mediastinum. N a = N o -- No tumor infiltration into the regional lymph nodes.

147

K. K a r r e r et al.: C h e m o t h e r a p y as an A d j u v a n t to Surgery in L u n g C a n c e r N b = N 1 -N e = N 2M0Ma = M+ --

Feinstein categories are classified a c c o r d i n g to the definitions published. In short: G r o u p 1 - D i a g n o s i s at r a n d o m , no s y m p t o m s before. G r o u p 2 - P u l m o n a l s y m p t o m s for more t h a n 6 months. G r o u p 3 - P u l m o n a l s y m p t o m s for less t h a n 6 months. G r o u p 4 - Same as g r o u p 2 plus e x t r a p u l m o n a r y s y m p t o m s . G r o u p 5 - S a m e as group 3 plus e x t r a p u l m o n a r y s y m p t o m s .

T u m o r cell infiltration into the regional bronchopulm o n a l l y m p h nodes. T u m o r cell infiltration into the t r a c h e o b r o n c h i a l (mediastinal) l y m p h nodes. N o evidence of distant metastases. D i s t a n t m e t a s t a s e s present including scalene, cervical or contralateral hilar l y m p h nodes and m e t a s t a s e s to brain, bone, or other organs.

The following T N M staging is used: Stage I Stage II Stage I I I TINaMo T2NaM 0

TxNbMo T2NbMo

A T1NaMo T2NaM0 TaNaM0

Stage IV

B TxNbM0 T2NbM0 T3NbMo

Results

T3NcMo T4Na,b,cMo TxNxM1

TxNcMo T2NcMo •T3Na,bM 0

Tables 1 and 2 show the number of patients grouped according to TNM stages, Feinstein categories, and three main carcinoma cell types (squamous-cell, adeno-, oat-cell and all others, i.e., "diverse" tumor types). "Diverse" histology means all other histological types than

C TI,2,3NcMo T4Na,b,cMo TxNxM1

Table l . N u m b e r of b r o n c h i a l c a r c i n o m a patients treated w i t h r a d i c a l s u r g e r y and a d j u v a n t c h e m o t h e r a p y Feinstein category

T N M stages

Total II

I

S

A

O

D

III

S

A

O

D

1

11

3

1

4

3

6

--

2 3 4 5 U

6 24 I 9 1

3 6 -2 1

I 1 -1 --

1 5 -2 --

5 13 1 6 1

1 8 -2 --

-3 -1 -

Total

52

15

4

12

29

17

4

Grand total

83 (36%)

S

--

O

D

S

--

1

3

5 9 2 6 1

-4 1 1 --

2 1 -1 1

---

27

6

6

1 --

54 (24%)

A 4

2 1

4

IV

A

O

--

3

1 ---

2 12 2 8 1

-5 1 2 --

4

25

11

43 (19%)

D

-

1

1 6 -

1

1 2

40 30 100

-

9

-

43

-

1

8

7

5

49 (21%)

229 (100%)

S = Squamous-cell c a r c i n o m a ; A = A d e n o c a r c i n o m a ; O = Oat-cell c a r c i n o m a ; D = Diverse c a r c i n o m a s U = Feinstein c a t e g o r y u n k n o w n

Table 2. N u m b e r of bronchial c a r c i n o m a patients treated with radical surgery only and used as r a n d o m i z e d controls Feinstein category

T N M stages

Total II

I

S 1 2 3 4 5 7

U Total Grand total

A

25 13 30 3 14 .

O

16 4 9 3 5 .

D

2 1 ---.

III

S 8 1 8 -2

.

A

4 3 11 2 4 .

.

O 6 3 2 1 2 .

D

1 2 4 -2 .

S --2 ---

.

IV

A 1

O

D

O

2

--

3

4

2

-6 -1

--

1

3

--

i

2

10

--

--

1

--

--

2

--

--

.

2

--

2

--

1

--

--

2

1

1

86

39

3

21

24

15

9

2

35

10

2

50 (17%)

A

4 15 2 11

1

149 (52%)

S

53 (18%)

. 6

1

-1 1

. 20

1 --

1

--

.

.

D 1 -5

5

S = Squamous-cell c a r c i n o m a ; A = A d e n o c a r c i n o m a ; O = Oat-cell c a r c i n o m a ; D = D i v e r s e c a r c i n o m a s U -- Feinstein c a t e g o r y u n k n o w n

35 107

--

--

12

--

4

48

--

--

.

37 (13%)

76

1

10 2

10 289 (100%)

148

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

the three main cell types already mentioned, and no "unknown" histological type is included in this group. In accordance with the Viennese School of Surgery the oatcell carcinomas are also included for surgery. A rather large number of patients are classified in T N M stages I and II; this might possibly be explained by the preselection of patients in private practice, which is essentially beyond our control. Most of these cases have been diagnosed as squamous-cell or adenocarcinomas. In the treated group as well as in the control group the age distribution shows a significant peak between the ages of 60 and 65 in both sex groups. Only a few patients older than 70 years of age were operated on. The male-female ratio was 1 : 5 . The percentage of asymptomatie patients (Feinstein category 1 shown in Tables 1 and 2) is quite similar to that of the original distribution recorded by Feinstein (1964), indicating that no particular measures of early diagnosis were effective. No explanation relevant to the statistical analysis can be given for the unequal number of 289 controls and 229 treated patients. Table 3 summarizes the infusions given to only 219 of the 229 randomized patients, as 10 randomized patients died postoperatively before chemotherapy. Detailed information is provided in Figures 1 through 5, where the occurrence of leucopenias is also documented. Alopecia, cystitis, and infections have been rare, so that they have been omitted from this preliminary evaluation. No second primary neoplasm has yet been observed. The treatment was well tolerated, causing only minor side effects such as vomiting and nausea for 1 - 2 days. Loss of hair and diarrhea were also rare. No patient required hospitalization due to side effects. Most of the patients stayed away from work only for the day of infusion. It seems particularly important that the rate of leucopenia appears lower than a comparably high-dosed

single-drug therapy would cause. Table 3 and Figures 1 - 5 also demonstrate the important finding that only 25 of 219 patients developed leucopenia below the leucocyte level of 2000/mm 3. Spontaneous recovery from leucopenia was seen in most cases, and only in some cases was the administration of cortisone and/or a blood transfusion necessary. Only a few patients received antibiotics and gammaglobulin prophylactically. It seems important that the occurrence of leucopenia during one treatment period is often followed by normal acceptance of the same treatment given later (Figs. 1-5). Chemotherapy was always begun and administered according to the protocol in hospital after operation. Continuation of this intermittent chemotherapy was followed much more rigorously by those patients living in the city of Vienna than those living outside Vienna, as already mentioned above. Regarding the relationship of the number of deaths caused by the tumor or on the other hand by other diseases, after careful consideration of deaths of unknown cause (all patients without autopsy) we feel that no further information significant for the conclusions of this preliminary evaluation is decisive. If the actual causes of death had been known, we would have subdivided these patients by of death. However, as the number of unknown causes of death (as seen in Tables 4 and 5) is so great, it was not meaningful to subdivide this group into individual causes of death for calculation of the life-table curves. The crude survival rates of the patients are calculated according to the life-table method. The number of patients at the time of operation, 36, and 60 months thereafter represents the number of patients at risk at this given time. The survival rates of patients with combined treatment and those of the control patients are subdivided into T N M stages I--IV (Fig. 6) and A, B, C (Fig. 7) (see also Tables 6 and 7).

Table 3. Bronchial carcinomas treated by radical surgery: patients with or without leucopenia after chemotherapy Leucocytes not below

TNM stages II

I

III

Total

Grand total

IV

No. of patients

Total no. of infusions

No. of patients

Total no. of infusions

No. of patients

Total no. of infusions

No. of patients

Total no. of infusions

Patients

Infusions

2000

71

892

47

545

40

380

36

1500 1000 700

3 5 1

17 57 11

5 --

79

-2 --

--

-

2

326 41 32

194 13 9

2

10

2143 137 141 21

Total

80

977

52

624

42

432

45

409

5

52 -

3

219

2442

149

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

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K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

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Table 4. Bronchial carcinomas treated by radical surgery and subsequent chemotherapy, subdivided into T N M stages and classed according to cause of death T N M stages

Total

I

II

III

IV

Total no. of patients

83

54

43

49

229

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45

11

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79

Died of: Postoperative complications Tumor Caehexia Suicide

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K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

151 III-T2 N c

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53

37

289

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92

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127

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K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

152

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Fig. 6. Comparison of life-tables from patients receiving/not receiving adjuvant chemotherapy after radical surgery for bronchial carcinomas: -chemotherapy group; - - - randomized controls

153

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

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Fig. 7. Comparison of life-tables from patients receiving/not receiving adjuvant chemotherapy after radical surgery for bronchial carcinomas: -chemotherapy group; - - - randomized controls

Table 6. Numbers of patients operated on 60 months or more ago and numbers and percentages of survivors at 60 months after surgery Group

Treated

Controls

P value a

Patients

Survivors

%

Patients

Survivors

%

To Figure 6 TNM I T N M II T N M IlI T N M IV

30 17 15 23

13 2 4 5

43.3 11.8 26.7 21.7

45 22 19 10

20 4 5 0

44.4 18.2 26.3 0

> > > >

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32 25 28

15 4 5

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49 31 16

21 5 1

42.9 16.1 6.3

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a p value according to the Fisher-test (Fisher, 1969)

Table 7. Numbers of living patients and their median observation time and numbers of deceased patients and their median survival time Group

Deceased patients No. of patients

Living patients

Median survival time in months before demise Treated

Controls

No. of patients

P value a

No. of patients

Observation time in months after operation Treated

Controls

No. of patients

To Figure 6 TNM I T N M II T N M III T N M IV

38 43 28 41

15 18 9 6

11 11 8 6

58 35 36 34

> > > >

0.1 0.1 0.1 0.1

45 11 15 8

41 11 32 56

28 15 20 6

91 15 17 3

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41 54 55

12 14 6

11 11 6

69 43 50

> 0.1 > 0.1 > 0.1

49 18 12

41 30 35

28 17 6

101 19 7

a p value according to the Wilcoxon-test (Wilcoxon et al., 1969)

P value a

> > > >

0.1 0.1 0.1 0.1

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154

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer Ctassifications

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Fig. 9. Comparison of life-tables from patients receiving/not receiving adjuvant chemotherapy after radical surgery for bronchial carcinomas. Feinstein classification: 2 + 4 and 3 + 5 chemotherapy group; - - - randomized controls The steepness of the curves (Figs. 6 and 7) demonstrates that the prognosis worsens with advancing T N M stage. These findings permit no significant statistical difference, but do support a passing tendency of improvement in some of these patients.

Figures 8 and 9 show the survival curves of the groups of the same patients, subdivided into Feinstein categories 1--5 and the 6th category termed "unknown". As seen in Figure 8, in the first group (Feinstein 1), i.e., in the patients randomly diagnosed as tumor-bearing, no positive trend can be seen in patients who received adjuvant chemotherapy. In the second group (Figs. 8 and 9) (Feinstein 2 and 2 + 4), i.e., that of patients with slow-growing tumors, this therapy seems to decrease the survival rate of the treated group. The third group (Feinstein 3 and 3 + 5), i.e., patients with fastgrowing tumors, shows a slightly positive trend favoring the group who received the combined therapy. This demonstrates that there is a correlation between the Feinstein categories and differences in prognosis and in sensitivity to the chemotherapy given. As seen in Figures 8 and 9, the slower-growing tumors (Feinstein categories 2 and 4) have a better prognosis than the faster-growing tumors (Feinstein categories 3 and 5). However, the sensitivity to the chemotherapy used shows the opposite. Figure 10 demonstrates the different effectiveness of this adjuvant chemotherapy on the patients of histo-

155

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer Table 8. Numbers of patients operated on 60 months or more ago and numbers and percentages of survivors at 60 months after surgery Group

Treated

Controls

P valuea

Patients

Survivors

%

Patients

Survivors

%

To Figure 8 F 1 F 2 F 3 F 4 F 5 F unknown

10 10 35 3 22 5

3 3 11 0 5 2

30.0 30.0 31.4 0 22.7 40.0

22 15 34 5 15 4

4 11 9 1 4 0

18.2 73.3 26.5 20.0 26.7 0

> 0.1 0.05 > P > 0.01 > 0.1 > 0.1 > 0.1 > 0.1

To Figure 9 F 2 + 4 F 3+ 5

13 57

3 16

23.1 28.1

20 49

12 13

60.0 26.5

0.05 > P > 0.01 > 0.1

a p value according to the Fisher-test

Table 9. Numbers of living patients and their median observation time, and numbers of deceased patients and their median survival time Group

Deceased patients No. of patients

Living patients

Median survival time in months before demise Treated

Controls

No. of patients

P valuea

No. of patients

Observation time in months after operation Treated

Controls

No. of patients

P valuea

To Figure 8 F 1 F 2 F 3 F 4 F 5 F unknown

26 22 65 7 26 4

16 11 9 6 8 12

12 7 8 4 8 8

38 16 62 7 33 5

> > > > > >

0.1 0.1 0.1 0.1 0.1 0.1

14 8 35 2 17 3

26 40 41 9 36 47

27 67 13 15 25 5

38 19 45 5 15 5

> 0.1 > 0.1 0.01 > P > 0.005 > 0.1 0.1 > P > 0.05 0.1 > P > 0.05

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29 91

9 9

7 8

23 95

> 0.1 > 0.1

10 52

37 41

57 18

24 60

> 0.1 0.001 >P>0.0001

a p value according to the Wilcoxon-test

logically different g r o u p s w i t h o u t r e g a r d to T N M staging or Feinstein categories (cf. T a b l e s 10 and 11). In F i g u r e 11 o n l y t h o s e patients are included w h o u n d e r w e n t radical surgery a c c o r d i n g to histological evidence, i.e., with no t u m o r at the cut surface, with (N÷) or w i t h o u t (No) t u m o r cells in the regional l y m p h n o d e s and with no e v i d e n c e o f distant metastases. In the u p p e r r o w the life-table c u r v e s o f the g r o u p o f patients with histologically p r o v e n e v i d e n c e o f the absence o f a n y t u m o r - c e l l i n v o l v e m e n t o f the regional l y m p h n o d e s (No) are d e m o n s t r a t e d , subdivided a c c o r d ing to the three m a i n categories o f histology: s q u a m o u s cell, adeno-, a n d all o t h e r t y p e s o f c a r c i n o m a s . In the

lower r o w the c o r r e s p o n d i n g fife-table c u r v e s o f the g r o u p o f patients with t u m o r - c e l l i n v o l v e m e n t o f the regional l y m p h nodes (N+) are shown. T h e benefit o f c o m b i n e d t r e a t m e n t in patients with oat-cell c a r c i n o m a s and with the o t h e r different histological types ( " d i v e r s e " ) o f c a r c i n o m a s c a n be seen. H o w ever, no beneficial effect c a n be seen in the g r o u p o f patients with s q u a m o u s - c e l l or a d e n o c a r c i n o m a s . F i g u r e 12 depicts the life-table curves o f the selected patients in Feinstein categories 3 and 5, i.e., fast-growing t u m o r s , subdivided into T N M stages I, II, III, and IV. W i t h i n the s u b g r o u p s d e m o n s t r a t e d in F i g u r e 12, a t e n d e n c y for the t r e a t m e n t to be beneficial c a n be seen

156

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

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Fig. 10. Comparison of life-tablesfrom patients receiving/not receiving adjuvant chemotherapy after radical surgery for bronchial carcinomas: Histological types: - - chemotherapy group; - - - randomized controls

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in all stages. Figure 13 shows the same patients as in Figure 12, but subdivided into the three histological main groups. See also Tables 12 and 13. It is of interest that there seems to be a positive tendency, even in the groups with squamous-cell carcinomas. The subdivision of the squamous-cell carcinomas

Fig. 11. Comparison of life-tables from patients receiving/not receiving adjuvant chemotherapy after radical surgery for bronchial carcinomas, subdivided by histological type and according to No or N+: - - chemotherapy group; - - randomized controls

by degree of histological differentiation expressed by the presence or absence of keratinization results in an apparent difference between these two groups. The group with keratinization shows a more favorable prognosis, whereas it shows a lower sensitivity to the chemotherapy used.

157

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer Table 10. Numbers of patients operated on 60 months or more ago and numbers and percentages of survivors at 60 months after surgery Group

Treated

To Figure 10 Squamous-cell Adeno Oat-cell Diverse To Figure 11 TxN0 Squamous-cell Adeno Oat-cell + Diverse TxN+ Squamous-cell Adeno Oat-cell + Diverse

Controls

P valuea

Patients

Survivors

%

Patients

Survivors

%

52 18 8 7

16 5 3 0

30.8 27.8 37.5 0

62 21 5 8

23 4 0 2

37.1 19.0 0 25.0

> > > >

23 10 3

12 4 1

52.2 40.0 33.3

34 12 4

15 4 2

44.1 33.3 50.0

> 0.1 > 0.1 > 0.1

18 5 10

3 0 2

16.7 0 20.0

26 7 7

8 0 0

30.8 0 0

> 0.1 > 0.1 > 0.1

0.1 0.1 0.1 0.1

" P value according to the Fisher-test

Table 11. Numbers of living patients and their median observation time and numbers of deceased patients and their median survival time Group

Deceased patients No. of patients

To Figure 10 Squamous-cell Adeno Oat-cell Diverse To Figure 11 TxNo Squamous-cell TxNo Adeno TxNo Oat-cell + Diverse TxN+ Squamous-cell TxN+ Adeno TxN+ Oat-cell + Diverse

Living patients

Median survival time in months before demise

No. of patients

P values

Treated

Controls

83 37 16 14

10 12 8 8

11 9 9 6

93 34 14 21

> > > >

0.1 0.1 0.1 0.1

32

8

12

50

> 0,1

10

23

9

16

0.05 > P > 0.01

7

9

5

9

36

20

14

19

12

17

9

No. of patients

Observation time in months after surgery

No. of patients

P valuea

Treated

Controls

50 12 6 11

38 54 39 29

33 21 6 8

72 35 2 18

> 0.1 0.005 > P > 0 . 0 0 1 > 0.I 0.05 > P > 0 . 0 1

33

40

33

58

> 0.1

7

64

24

27

0.05 > P > 0.01

> 0.1

12

38

8

16

0.05 > P > 0.01

31

> 0.1

13

13

33

11

> 0.1

7

14

> 0.1

4

46

9

7

0.1 > P > 0 . 0 5

8

19

> 0.1

4

17

11

2

> 0.1

a p value according to the Wilcoxon-test

158

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

100 ~

I

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ii

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58

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Fig. 12. Comparison of life-tables from patients receiving/not receiving adjuvant chemotherapy after radical surgery for bronchial carcinomas. Feinstein categories 3 and 5, subdivided into T N M stages: -chemotherapy; - - - randomized controls

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Fig. 13. Comparison of life-tables from patients receiving/not receiving adjuvant chemotherapy after radical surgery for bronchial carcinomas. Feinstein categories 3 and 5, subdivided into histological types: -chemotherapy; - - randomized controls

1t

1'2:2Z, 3"6 z,~3 60 48 60 months after operation

12

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Table 12. N u m b e r s of patients operated on 60 months or more ago and numbers and percentages of survivors at 60 months after surgery Group

Treated Patients

To Figure 12 TNM I T N M II T N M I I I + IV To Figure 13 Squamous-cell Adeno Oat-cell + Diverse

Controls Survivors

%

Patients

P value a Survivors

%

18 12 27

9 1 6

50.0 8.3 22.2

17 14 18

8 3 2

47.1 21.4 11.1

> 0.1 > 0.1 > 0.1

35 11 11

12 2 2

34.3 18.2 18.2

33 9 7

8 3 2

24.2 33.3 28.6

> 0.1 > 0.1 > 0.1

a p value according to the Fisher-test

159

K. Karrer et al.: Chemotherapy as an Adjuvant to Surgery in Lung Cancer

Table 13. Numbers of living patients and their median observation time and numbers of deceased patients and their median survival time Group

Deceased patients No. of patients

Living patients

Median survival time in months before demise

No. of patients

P value"

Treated

Controls

To Figure 12 TNM I 21 TNM II 26 TNM III+ IV 44

9 21 7

10 12 7

27 20 48

> 0.1 > 0.1 > 0.1

To Figure 13 Squamous-cell Adeno

50 22

9 10

12 4

60 14

19

7

8

21

Oat-cell + Diverse

No. of patients

Observation time in months after operation

No. of patients

P valuea

Treated

Controls

29 9 14

42 22 35

21 6 14

41 7 12

> 0.01 > P > 0.005 > 0.1 > 0.1

> 0.1 37 > 0.1 8 > P > 0.05 > 0.1 7

38 51

21 8

37 13

> 0.1 > 0.05 > P > 0.01

36

14

10

> 0.1

a p value according to the Wilcoxon-test

Conclusion

The adjuvant chemotherapy described was well tolerated. I n some cases the therapy was discontinued for other reasons, mostly because patients in Austria are not informed of their diagnosis. This preliminary evaluation of combined treatment certainly encourages the continuation of this kind of study. Considering the variety of prognostic factors and the types of tumors involved, including differences in the sensitivity to a given drug combination and/or dose, it might become necessary and/or advantageous to select various other therapeutic agents, which act as specifically as possible on the different kinds of tumors. The results shown seem to support the hypothesis that the dose schedule used was not adequate for slow-growing tumors and for squamous-cell and adenocarcinomas. Therefore, it seems advantageous to change the dose schedule or the combination of drugs used for the adjuvant treatment for this group of tumors. This does not necessarily mean that the dose used is optimal for fastergrowing tumors. The tendencies observable in the results of this pilot study suggest more promising findings from and the ne-

cessity of further protocols of larger cooperative international groups.

References

Arnal, M. L., Dold, U., Ehlers, C. Th., GSgler, E., Hamperl, H., Karrer, K., Oberhofer, G., Ott, G., Pascher, W., Proppe, A., Scheibe, O., Sehmolling,E., Spiessl, B., Thurmayer, R., Wildner, E. P.: Zur Klassifizierungder Gesehwulstkrankheiten.Der ,gesicherte" TNM-Schhissel(Erweiterungsvorschlagzu den ,,General Rules" der UICC). Meth. Inform. Med. 6, 70 (1967) Feinstein, A. R.: Symptomatic patterns, biologicbehavior and prognosis in cancer of the lung. Ann. intern. Med. 61, 27 (1964) Fisher, R. A.: Fishers exakter Vierfeldertest. In: Statistische Auswertungsmethoden. Sachs, L., (Ed.), p. 365. Berlin-HeidelbergNew York: Springer 1969 Karrer, K., Denck, H.: Weitere Vorschlgge zur chemotherapeutischen Rezidivprophylaxe des Bronchuskarzinoms. Wien. med. Wschr. 17, 121 (1971) Kreyberg, L., Liebon, A. A., Uehlinger,E. A.: International histological classification of tumors. 1. Histological Typing of Lung Tumors. Geneva: WHO 1967 Wilcoxon, F., Mann, H. B., Whitney, D. R.: U-Test. In: Statistische Auswertungsmethoden. Sachs, L. (Ed.), p. 293. Berlin-Heidelberg-New York: Springer 1969 Received July 13, 1977/Accepted April 5, 1978