Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer

P,xliotherapy and Oncology. I3 (19xX) X3 X9 Elscvicr

83

RTG 00502

eerI

EM. Noordijkl, E. v.d. Pocst Clementl, J. Hermansz, A.

(Received 14 .lanuary 19Xx. revision rcccived IX April 198X. accepted 25 April 1988)

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Lung CB~CCP;Radiotherapy; Resection

Summary From 1978 to 1983, 50 patients with a peripherally located non-small cell tumor of the lung were irradiated with curative intent. These patients were not operated upon because of poor cardiac or pulmonary condition, old age or refusal to operate. Mean age was 74 years, 40 patients being over 70 years of age. All patients bad T1_2NOM0 tumors according to the AJC classification and received 60 Gy to the primary tumor only. The overall response rate was 90%. with 50% complete responses in tumors smaller than 4 cm. The crude overall survival rates were 56% at 2 years and 16% at 5 years. with a median survival of 27 months. Age did not influence survival. There was a strong correlation of survival to tumor size, with 5-year survival rates of 38, 22, 5 and 0% in tumors with diameters of 62, 2-3, 3-4 and >4 cm respectively. Only 5 out of 20 complete responders had a local recurrence, the S-year survival in this group was 42%. These results compared favorably to a group of 86 patients over 70 years of age who were selected for operation in the same hospital. The 2- and 5-year survival rates in these patients were 48 and 26% respectively, median survival being 23 months. We conclude that in patients over 70 years of age with resectable lung cancer, radiotherapy with curative intent should be offered as an alternative to operation, especially if the tumor is not larger than 4 cm. The wait-and-see policy in inoperable patients of this age group must be abandoned.

Introduction The role of curative radiotherapy in the treatment of lung cancer is controversial. Occasionally cure is reported in patients with small, resectable tumors Address

.for correspondence: E. M. Noordijk

(radiotherapist).

Department of Clinical Oncology. University Hospital, Building

I, KI-P.

P.O. Box 9600, 2300 RC Leiden, The Netherlands.

0167-8140/88/$03.50

0

after high dose radiation therapy [3,11,I 21.Surgery, however, still is considered the treatment of choice for localized non-small cell lung cancer and radiotherapy is only used, if sur’gery is contraindicated for medical reasons or is refused by the patient. In patients above 70 years the expected S-year survival advantage of surgery over radiotherapy has to be reduced by the operation mortality. which has been reported to be 4-14% for this age group

1988 Elsevier Science Publishers B.V. (Biomedical Division)

84 [ 1,2,4,6,13]. If purvival potential after curative radiotherapy for operable tumors is proven to be comparable with surgery, radiotherapy could be an attracti.ie alternative to surgery for patients above 70 years with operable tumors. In this report, the results of radiotherapy with curative intent in 50 patients with “operable” tumors are presented. We suggest a new alternative strategy for the treatment of resectable bronchial carcinoma in the elderly.

TABLE I Characteristics of 50 NSCLC patients. Rcu.wttz.~ IO wfruita frot?t otpwatirttt:

high operative risk bilateral tumor older age patient’s refusal scs male

Patients and methods

From 1978 to 1983, 1033 patients with lung cancer were treated at the Department of Radiotherapy, University Hospital, Leiden. Among them were 50 patients with resectable peripheral tumors, that were medically inoperable or refused operation. These patients received radical radiotherapy with curative intent, after they met the following criteria for curative treatment:

(1) T1 or peripheral Tz. No. M. according to the AJC classification. assessed by chest X-rays and CT-scans (2) non-small cell carcinoma (3) Karnofsky performance status greater than or equal to 80%. Some characteristics are listed in Table I. Mean age was 74 years, with 4Q patients (80%) being over 70 years of age. In 44 patients the diagnosis was confirmed histologically or cytologically and in the six patients with a clinical diagnosis only, there was evidence of growth of the tumor on consecutive chest X-rays. The largest diameter of ail tumors on chest X-rays was reassessed. Half of the patients had a TI and the other half had a Tz lesion. All patients were irradiated with a linear accelerator using a split-course technique. Two courses of 10 x 3 Gy in 2.5 weeks each were given, to a total tumor dose of 60 Gy. The target volume comprised the primary tumor only and no mediastinal or hilar irradiation was considered. Usually a twofield technique with correction for lung density was

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65-69 70-74 75-79 3 80 Tittttor &ttttcYcr

8 14 17 9 (m I

G2 2-3 3-4 >4 _.____.__-_ __---

8 I7 25 T, I5 25 I.2 I(! .--- - ----

used. In all patients the response of the tumor was scored (complete response, partial response or no change) according to the WHO criteria. Survival analyses were performed, studying different prognostic factors.

Results

All patients but one received the planned total dose of 60 Gy. One patient developed brain metastases in the split period and did not receive the second part of 30 Gy. A patient with bilateral tumors received 60 Gy on both tumors. The response rate according to tumor size is listed in Table II. All 25 tumors smaller than 3 cm showed a complete or partial response; 39 out of the 40 patients with tumors smaller qhan 4 cm showed a response. No complete responses were seen in tumors larger than 4 cm. The overall response rate (CR and PR) was 90%.

TABLE

II

___-__ Diameter

II

~.~_

.____

CR

PR

Response rate (“/a)

ml)

il

%,

-<2

8

5

Z-3

17

3-4

I5 IO

>4

II

___-

63

3

x

47

9

7

47

7

0

0

6

I I1 (Nz75) I’ 1 ,? ( N .‘!I )

Crude survival rates were calculated according to age, T-classification and response (Figs. 1,2 and 3). Age did not prove to be a significant prognostic factor for survival. The influence of T-classification (T, vs. Tz) on survival was of borderline significance. Because of the relationship between response rate and tumor diameter mentioned above, survival was also plotted against tumor diameter. Rearrangement of the groups into tumors smaller or larger than 4 cm showed a very significant difference 01 = 0.007) with a median survival of 32 months vs. 12 months (Fig. 4). The 5-year survival of patients with a complete response was 42% (Fig. 3).

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60

Months

Fig. 2. T-~hssili~~thn ilIld survival.

1 < 70 year (N= 10) 2>~7Oyear (N=40)

1 CR (N = 20) 2 PR +NC (N.28)

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24

36 Months

Fig. I. Age and survival.

40

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60

00 t

12

24

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Months

Fig. 3. Rcsponsc and survival.

l-l-l

A comparison in survival was made between the 50 irradiated patients and all 86 patients of 70 years or older, that were operated for lung cancer from 1969 to 1980 in the University Hospital, Leiden. Although this comparison has all the drawbacks of a retrospective analysis, the lack of difference in the two survival curves (Fig. 5) and in the year-to-year and median survival figures in both groups over 70 years (Table III) is striking.

The disease status of the 50 patients is illustrated in Fig, 6. All30 patients that did not achieve a complete response died within 5 years with a mean survival time of 20 months. In the group of 20 patients with a complete response, 3 died of local and 3 of distant tumor progression; 6 patients died of unrelated causes. At the time of this analysis, 8 patients were still alive, 6 with no evidence of disease (NED) (mean survival 65 months) and 2 with local progression (mean survival 58 months). In the group of 36 patients that died From or with cancer, 11 patients died From progression of their primary tumor alone. None died of regional (hilar or mediastinal) metastases alone. Thirteen patients died from distant metastases or generalized disease, Eleven patients died with cancer but primary cause

1<=4CM 2 54CM

1 Radmtherapy (N : 50) 2 Surgery >=MYRS(N=86) p aO.10

12

0

24 Months

36

48-0

Fig. 5. Type of treatment and survival.

of death was intercurrent disease (especially cardiac, 7 times). One patient died of a second primary outside the lung.

There were no serious early or late side effects of irradiation. Radiation fibrosis was frequently seen on regular chest X-rays, but was never symptomatic. The small-field technique did not interfere with respiratory reserve.

(Ns40) fNz10)

TABLE

111

Survival for elderly ( >, 70 years) NSCLC patients treated with curative radiotherapy or operation.

Time

Radiotherapy

Operation

interval

II = 40

)l

6 months

93%

84%

=

86 -

0, 0

12

24

36

48

I 60

I year

70%

71%

2 years

55%

48%

3 years

32%

39%

4 years

21%

29%

5 years

15%

26%

Median

27 months

23 months

Months

Fig. 4. Tumor diameter and survival.

87

P

30 No complete response

Local faibre 3 Distant failure 3 Intercurrent 6 (NED)

Local failure 2 NED 6

03

q

: Alive

Fig. 6. Discascstatus ol’ 50 NSCLC palicnts. trcittcd wih CUTativc ntdiothmpy.

The complete and partial response rates in our 50 patients (40 and 50% respectively, overall response rat: 90%) are better than the rates usually reported with a radiation dose of 60 Gy, for example, in the RTOG studies [8,9]. This is probably due to the relatively large proportion of small tumors in our material, only IO being more than 4 cm in diameter (Table I). Perez et al. [8] reported more complete responses in tumors with diameters of l-3 cm (20%) than in those of 4-6 cm (12% after 60 Gy. We found a very significant difference in survival between tumors of less than 4 cm and more than 4 cm in diameter (Fig. 4). Coy and Kemlelly [3] reported 3-year survival rates of 26, 20 and 14% in patients with tumors less than 3 cm, from 3 to 5 cm and larger than 5 cm respectively. Ultimately local control is the determinate of survivai in patients who do not develop metastases [I I ] and obviously the tumor size is correlated with the possibility of obtaining this local control, especially in clinical No M. patients. Several authors have pointed out that tht: local control rate is dose-dependent [S--l 11.The RTOG studies show a clear advantage of 60 Gy over 50 Gy and 40 Gy, with intrathoracic in-field failure rates of 27, 38 and 48% respectively [9]. Sherman et al. [ 111found a 50% failure rate for doses of less than

50 Gy and a 5% failure rate for doses of 60 more. Schaakc-Koning et al. [IO] reported belter local control rates with doses of 65 Gy or more. We defined local control as the permanent disappearance of the primary tumor during life. This permanent local control was accomplished in 15 out of 50 patients (30%). On the other hand, only BI patients (22%) died from their primary tumor alone. This means that 23 patients (48%) died from causes outside the radiation field. i.e. from distant rnetastases (X0/o), intercurrent disease (22°h) or ;I second primary (one patient). It is possible that ;I higher total dose than the one we used (Ibr example 65 Gy, as suggested by Schaakc-Koning et al., [IO]) could reduce the number of local rcc~~rr~“~~ccs, but still about 50% of the patients will die of distant metastases or of intercurrent, age-related disease. The crude survival rate at 5 years (16%) confirms the old observation of Smart [12] that cure by irradiation alone is possible in selected cases. In patients in whom a complete remission was induced. the survival at 5 years was 42% (Fig. 3). which in view of what was stated above is about the maximum to be accomplished for a local treatment as radiation therapy. Coy and Kcnnelly [3] reporled a S-year survival of 45% in complctc respondcrs (our series: 65%). In our scrics an age 1xAow OI above 70 years did not have an influence on survival (Fig. I). Our 3- and 5-year survival rates in patients over 70 years (32 and 15%) compared well with those reported by Coy and Kennelly [3] of 23 and 17% respectively. Although in general the life expectancy of a 70year-old male is I I years and of an 80-year-old malt 7 years [13]. the life expectancy of a 70-year-old male cured of lung cancer is less, because of coexisting diseases like chronic obstructive pulmonary disease and cardiovascular

changes,

usually en-

countered in heavy smokers. This means that a significant part of death causes in elderly lung cancer patients consists of intercurrent discascs. Chronic lung and heart diseases inletferc with surgory in IWO ways: (I) they will preclude surgery because of the high mortality risk

88 (2) if surgery is performed, morbidity and mortality will be higher than normal. The major causes of death after lung cancer surgery in the elderly are: pneumonia, respiratory failure,

bronchopleural fistula, empyema, myocardial infarction and pulmonary embolus. In reports from 1970 to 1980, operation mortality rates for elderly patients were given ranging from 13 to 23% [4], but after 1988 some authors report better results, from 4 to 14% (Tdbic iv). These figures are important in the comparison of surgery and radiotherapy in elderly lung cancer patients, because operation trades short-term survival against long-term survival, increased long-term survival being obtained at the expense of the operative mortality rate [5]. The difference between “modern” S-year survival after lobectomy (f 35%, see Table IV) and the 5year survival in our patients (15%) therefore should be reduced by an operative mortality rate of 710%. A real comparison between surgery and radiotherapy in operable lung cancer in the elderly is virtually impossible. The only randomized study on this subject, conducted by Morrison et al. in 1954-1958 [7], showed a 4-year survival rate after surgery of 23% (which is low) and a 4-year survival rate after radiotherapy of 7% (which is much too low, probably because of the low radiation dose of 45 Gy). The comparison we made between 50 irradiated patients and 86 operated patients of 70 years or older (Fig.5, Table III) was neither randomized nor prospective. There was a deliberate selection into TABLE

relatively “healthy” patients that were operated if allowed by the patients. Those with high risks were irradiated. Both operation (lobectomy and pneumonectomy) and radiotherapy can be considered to be carried out with maximum potential for cure. The 4-year survival rates after surgery and rddiotherapy (29 and 21% respectively) are better than those of Morrison et al. [7]. The slightly better survival rates in the first 2.5 years in the radiotherapy group reflect on operative mortality rate of only 5%.

The quality of life aspects [5] in the treatment of the elderly lung cancer patient must not be disregarded, Even if one dOtis so it is clear that curative radiotherapy must be taken into account while the scenario of informed consent is considered. The statement of Yellin and Benfield [13]: “every lung cancer patient whose disease is apparently limited to the chest should have the opportunity to discuss the risks and benefits of operation with an experienced knowledgeable thoracic surgical consultant” needs to be extended to: “and should have the opportunity to discuss the possibilities of radiotherapy with an experienced radiation oncologist”.

(1) Radiotherapy can play a curative role in elderly lung cancer patients with operable peripheral tumors smaller than 4 cm. (2) Patients should be informed properly on the advantages and disadvantages of surgery as well as radiotherapy. There is still a place for a prospective random(3)

IV

Qpruion mertalityand Author

S-year survival after resection in the elderly (after 1980).

Year

Operation

S-Year

mortality (%)

survival (%)

Remarks

Brayer et al. [2]

1981

I50

4

42

Lobectomies

Ginsberg et al, [4] BergEn et al. [I] Yellinand Benfield [ 131

1983 1984 1985

453 82

7 I4

32

L.C.S.G. data

58

7

35

Mensen et al. [6]

1986

60

5

37

Lobectomies Lobectomies

89 ized trial comparing operation and radiotherapy in these patients. (4) The wait-and-see policy if surgery is not possible must be abandoned.

6 Mcnsen. E. A P. M.

M..

Dekhuijzen. P. N. R.

and

Wagenaar, J.

Rcscctic wegens bronchuscarcinoom bij patienten

ouder dan 70Ja;ir. Ned. Tijdschr. Gcneeskd. 130: 1672, 1986. 7 Morrison. R.. Dccley. T. 3. and Cleland. W. P. The treatment ;,f carcincxna of the bronchus. Lnncet I: 683-684. 1963. 8 Perez. C. A.. Stanley. K.. Grundy. G.. Hanson. W.. Ruhin. P.. Kramer. E.. Brady. L. W.. Marks, J. E., Perez-Tamayo.

eferences

R.. Firown. S.. Cancannon. J. P. and Rotman. M.

Impact

of irradiation technique and tumor extent in tumor control Berggren, H., Ekroth, R., Malmbcrg. R.. Naucler. J. and William-Olsson. G.

Hospital mortality and long-term sur-

vival in relation to preoperative function in elderly patients with bronchogenic carcinoma. Ann. Thorac. Surg. 38: 633Breyer, R. H.. Zippe. C.. Pharr. W. F.. Jcnsik. R. J.. Kittlc. C. F. and Faber, L. I’. Thoracotomy in patients over age scvcnly years. Ten-year cxpcricncc. J. Thorac. Cardiovasc. The role of curative radio-

therapy in the treatment of lung cancer. Cancer 45: 698-702. 1980. 4 Ginsberg, R. J., Hill, L. D.. Eagan. R. T., Thomas. P., Mountain, C. F., Deslauricrs. J.. Fry, W. A., Butz. R. 0.. Goldberg, M., Walers, P. F.. Jones, D. P.. Pairolcro. P., Rubinslein. L. and Pearson. J. G. Modern thirty-day operative mortality for surgical resections in lung cancer. J. Thorac. Cardiovasc. Surg. 86: 654-658. 1983. 5 McNeil, B. J.. Weichselbaum. R. and Paukcr. S. G. Fallacy of the five-year survival in lung cancer. 1397-1401. 1978.

cinoma of the lung Report by the Radiation Therapy Oncology Group. C’anccr 50: 1091-1099. 1982. 9 Perez. C. A.. Pajak, T. F., Rubin, P.. Simpson. J. R.. Mohiuddin. M.. Brady. L. W.. Perez-Tamayo, R. and Rotman.

636. 1984.

Surg. 81: 187-193, 1981. Coy, P. and Kcnnclly. G. M.

and survival of patients with unrcscctablc non-on! cell car-

N. Engl. J. Med. 295:

M.

Long-term observations of the patterns of failure in

patients with unrcscctill~le IlOll-Oitt Cdl

CiUTillOlllil

Of thC IUllg

trcatcd with definitive rtldiothcrapy. Report by the Radiation Therapy 011~0logy Group. Cancer 59: 1874-1881. 1987. IO Schaake-Koning. C.. Schuster-Uittcrhocvc, L., Hart. G. and Gonzales, D. 6.

Prognostic factors of inoperable localized

lung cancer trcatcd by high dose radiotherapy. In!. .I. Radiat. Oncol. Biol. Phys. 9: 1023-1028. 1983. II Sherman. D. M.. Weichselbaum, R. and Hellman. S. The characteristics of long-term survivors of lung cancer treated with radiation. Cancer 47: 2575-2580. 1981. I2 Smart. J. Can lung cancer be cured by irradiation alone‘? J. Am. Med. Assoc. 195: 1034-1035, 1966. I3 Ycllin. A. and Benfeld. J. R. Surgery for bronchogenic carcinomil in the elderly. Ann. Rev. Respir. Dis. I3 I: 197. 1985.