Local irradiation alone for peripheral Stage I lung cancer: Could we omit the elective regional nodal irradiation?

Int. J. Radiation

Oncology

Biol.

Phys., Vol. 34, No. 2. pp. 297-302, 1996 Copyright 0 1996 Elsevicr Saencc Inc. Printed in the USA. All rights reserved 0360.1016/96 $ IS.00 + .OO

ELSEVIER

0360-3016(95)00227-S

l

Clinical Original Contribution LOCAL IRRADIATION COULD WE OMIT AUGUSTINUS

ALONE FOR PERIPHERAL THE ELECTIVE REGIONAL

STAGE I LUNG CANCER: NODAL IRRADIATION?

D. G. KROL, M.D.,* PETER AUSSEMS, M.D.,* EVERT M. NOORDIJK, Jo HERMANS, PH.D.+ AND JAN W. H. LEER, PH.D.*

PH.D.,*

*Department of Clinical Oncology, University Hospital, Leiden, The Netherlands; and ‘Department of Medical Statistics, University of Leiden, Leiden, The Netherlands Purpose: The results of local irradiation only for patients with Stage I lung cancer were analyzed to see whether the treatment of regional lymph nodes could be omitted. Methods and Materials: One hundred and eight medically inoperable patients with nonsmall cell lung cancer (Tl and peripheral T2) were treated with 60 Gy split course or 65 Gy continuous treatment. The target volume included the primary tumor only, without regional lymph nodes. Response, survival, and patterns of failure were analyzed. Results: The overall response rate was 85% with 50 (46%) complete responses (CRs). Overall survival at 3 and 5 years was 31 and 15%, and cancer-specific survival was 42 and 31% at 3 and 5 years, respectively. The actuarial 5 years local relapse free survival in patients with a CR was 52%. Tumor size (14 cm) was strongly correlated with the chance of complete remission and better survival. Of patients in complete remission, only two had a regional recurrence as the only site of relapse; an additional two patients had a locoregional recurrence. Conclusion: High-dose local radiotherapy on the primary tumor only is justified for medically inoperable patients with peripherally located nonsmall lung cancer. The low regional relapse rate does not support the need for the use of large fields encompassing regional lymph nodes. Using small target volumes, higher doses can be given and better local control rates can be expected. Lung cancer, Stage I, Radiotherapy.

INTRODUCTION

these tumors in our institute for many years, we decided to analyze our material with special attention to this question. Since 1978, 108 patients with peripheral nonsmall cell lung tumors were treated with high-dose local radiotherapy and prospectively followed. An analysis of the first 50 of these patients, demonstrating the importance of tumor size for local control and indicating that radiotherapy might be a good alternative for surgery in the older age group with tumors smaller than 4 cm, was published in 1988 (12). In the present analysis special attention was paid to the local control rate and regional and distant relapse rates after local treatment.

Several studies (1,4-8, 12, 14, 15, 17, 18,20) have shown that high-dose radiotherapy is an acceptable alternative for surgery in patients with nonsmall cell lung cancer who are medically inoperable. In all of these studies except one (12), almost all patients were treated with large fields not only encompassing the primary tumor, but also the regional lymph nodes in the hilum and mediastinum. However, due to radiation-induced fibrosis, large fields can compromise the already limited lung function of these patients, especially when higher doses are used. For the subgroup of patients with peripherally located lung tumors without signs of regional metastasis after diagnostic work-up, the question arises whether the elective treatment of the regional nodes can be omitted (3, 16). Because local irradiation was the treatment policy for

METHODS

AND MATERIALS

Between January 1978 and 1992, a total of 108 patients with resectable peripherally located lung tumors were treated

Reprint requests to: Jan W. H. Leer, Department of Clinical Oncology, University Hospital, Leiden, P.O.B. 9600, 2300 RC Leiden, the Netherlands. E-mail: [email protected]

Accepted for publication 11 May 1995.

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Table 1. Patient and tumor characteristics of 108 patients with peripherally located lung tumors

Age

mean range Sex male female TNM classification (UICC 1987) TlNOMO T2NOMO Reason for no surgery* poor pulmonary function poor cardiac condition poor general condition patient refused unknown

74.2 years 56-88 103 5 51 57 71 37 6 6 7

* Some patients had more than one reason.

with local irradiation in our institute. The patients and tumor characteristics are shown in Table 1. As can be seen, most patients were of old age (mean 74.2 years). All patients had a Kamofsky performance of 70 or mom. All tumors were classified as being Tl or T2 according to the Union Intemationale Contre le Cancer (UICC) system (1987). The classification was based on chest x-rays, bronchoscopy, and computed tomography (CT) of the media&urn (86% of the cases). Because CT was introduced in 1978 in our hospital, a few patients in the earlier years of the study had conventional tomography in combination with an esophagram. Mediastinoscopy was not part of the work-up in these patients. The clinical and radiological diagnosis of malignancy was confirmed by histological examination in 67 patients and by cytology in 32; in 9 cases neither histology nor cytology were available because the risk of pneumothorax in combination with poor pulmonary function of the patient was considered unacceptable. However, these patients were in the follow-up of the puhnonologist, and had a growing mass on two consecutive chest x-rays. With respect to the reasons to refrain from surgery, six patients refused to be operated upon, although they were judged to be fit for operation. The great majority were considered to be inoperable, due to poor pulmonary function or cardiac or general condition. All patients were treated with megavoltage irradiation using a linear accelerator (5 MV). The target volume consisted of the primary tumor with a margin of about 2 cm and was mostly determined using a CT-based planning. The dose specified to the International Commission of Radiation measurements and Units (ICRU) reference point was either 60 Gy or 65 Gy. According to ICRU guidelines, the dose inhomogeneity did not exceed plus or minus 5%. Dose calculations were corrected for lung density. Before 1987,60 Gy (69 patients) was delivered in fractions of 3 Gy using 2 times 10 fractions in 2 weeks, with a split interval of 3 weeks. After 1987,65 Gy (39 patients)

Volume 34, Number 2, 1996

was given in a continuous schedule with 26 fractions of 2.5 Gy. After treatment was completed, patients were followed with three monthly intervals. At each visit, besides history and physical examination, a chest x-ray was made. Chest x-rays were considered suitable for follow-up, because due to the fact that patients were not irridiated on mediastinum or hilum, small changes could be detected. When changes on chest x-rays were observed or in case of doubt, standard procedures were supplemented with CT-scan and, if necessary, bronchoscopy. Tumor response was scored according to the WHO criteria for reporting results of cancer treatment. Chest x-rays were reviewed by two seperate investigators. This presented no problems as hardly any fibrosis was observed due to the small fields used. Disappearance of the tumor on chest x-rays was considered to be a complete response (CR) and 50% or more decrease in tumor size, as partial response. When a 50% decrease could not be established and a 25% increase in tumor size was not observed, response was classified as no change. Progressive disease was defined as 25% or more increase in tumor size or the appearance of new lesions. Overall survival and cancer-specific survival were calculated from the first day of treatment until death or last follow-up (January 1, 1994). Local relapse-free survival was calculated from the first day of treatment until local failure. Points of special interest in our analysis were influence of tumor size, age, and treatment schedule on local control of the primary tumor and patterns of failure after CR. Statistical analysis was performed using chi-square tests to compare percentages in cross tabulations and the log-rank test to compare Kaplan-Meier survival curves. RESULTS All patients but two received the planned dose; in one patient the treatment was interrupted at 30 Gy because of the appearance of brain metastases, and intercurrent disease caused the treatment interruption in the other patient at 5 1 Gy. Side effects were mild and never caused discontinuation of the treatment. Response and survival

Fifty patients had a CR and in 58 patients, treatment failed to induce a CR. Of these 58 patients, 42 had a partial response, 8 patients showed no change, and 6 had progression after irradiation; in only 2 patients was the assessment of response impossible due to severe pneumonitis (Table 2). At the time of this analysis (January 1994) 14 patients were still alive: 13 without evidence of disease and 1 with a recurrence. Thirty-two patients died of causes not related to cancer (e.g., myocardial infarction, stroke, and second malignancies),

of which

19 were in complete re-

Local irradiation alone for lung cancer l A. D. G. KROL et al.

Table 2. Responseto radiotherapyand eventsduring followup of 108 patientswith peripherally locatedlung tumors

Failure diseasefree local only local/regional local/distant local/regional/distant regionalonly distantonly PresentState alive no cancer-relateddeath cancer-relateddeath

Complete response (n = 50)

No complete response (n = 58*)

31 9 2 3 0 2 3

1’ 21 6 24 6 0 0

14’ 19 17

1+ 13 45

* 42 partial; 8 no change;6 progression;2 not evaluable. ’ after lobectomy. t One patient with recurrent disease.

mission at the time of death. When there was doubt about cause of death, death was scored as cancer related. Sixtytwo patients died due to tumor progression: 17 after first reaching CR and 45 who never were cleared from tumor (Table 2). The overall survival for all patients was 75% at 1 year and 3 1 and 15% at 3 and 5 years, respectively. Cancerspecific survival was 81%, 42%, and 3 1% at 1, 3, and 5 years (Fig. 1). The following factors were analyzed for their influence on response, overall survival, and cancerspecific survival: tumor size (tumors under or over 4 cm in diameter), treatment schedule (60 Gy split course vs. 65 Gy continuous irradiation), and age (below or over 75 years) (Table 3). Smaller tumors had a significantly higher CR rate than larger tumors (52 vs. 21%). Tumors of 4 cm or smaller had a better survival at 3 years than larger tumors, 35 vs. 11% and 40 vs. 13% for overall and cancer-specific survival, respectively. Treatment schedule and age had no influence on these endpoints.

299

than 4 cm with a complete remission (Table 3). Only two patients (4%) had a relapse in the regional lymph nodes as the only site, and three patients had isolated distant metastases (Table 2). All of the 58 patients not achieving complete remission had local progression. In 36 of them, regional and/or distant failure was also observed (Table 2). The incidence of distant metastases was strikingly higher in the group not reaching complete remission than in those with a complete disappearance of the tumor (52 vs. 12%, respectively). In both groups (complete remission or not) there was one patient who achieved a diseasefree status after lobectomy for a local recurrence. DISCUSSION We analyzed a group of 108 patients who were considered to be medically inoperable and who had been treated since 1978 with high-dose local radiotherapy and prospectively followed. In a previous publication the results of the first 50 of these patients were reported by Noordijk ef al. (12). A comparison of our results with those reported in the literature is shown in Table 4. Our present results are in agreement with those reported in the literature, and not different from the first 50 cases in this series. Only the results of Zhang et al. (20) seem to be better; however, in this series patients were younger (average age 57.1 years) and a substantial number were not operated upon because of patient refusal. Thus, a positive selection in this material seems very likely. In contrast to Haffty et al. (6) and Perez et al. (14), but in agreement with others (3, 8, 10, 11) we could not detect an influence of the two different treatment schedules, 60 Gy split course with a fraction size of 3 Gy and 65 Gy continuous irradiation with a fraction size of 2.5 Gy. In the 108 patients in this study who were considered to be unfit for surgery (only 6 refused operation), the CR rate was 46%. For those who achieved complete remis-

100

SURVIVAL

Failure analysis

For this analysis, the patients who achieved and did not achieve a complete remission were considered separately. Of 50 patients who achieved a CR, 31 (62%) had persistent local control. The actuarial local relapse-free survival at 1, 3, and 5 years was 96%, 7 1% and 66%, respectively. Nine patients had a local recurrence as the only site of tumor progression. Local failure in combination with regional relapse was seen in two patients, and another three patients had a local recurrence in combination with distant metastasis. When local relapse rate was correlated to initial tumor size, no difference was found between tumors smaller or larger than 4 cm, p&ably due to the limited number of patients with tumors larger

0 / 46

0

12

24

60

72

M&S

Fig. 1. Survival of 108StageI lung cancer patients treated with local irradiation.

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Table 3. The influence of tumor size, treatment schedule, and age on response rate and survival of 108 patients with peripherally located lung tumors N Total Tumor size 5 4 cm > 4 cm

CR rate (%)

3 years CSS (%)

108

N

3 years LRFS (%)

50

89 19

52 21 0.03

35 11 0.003

40 13 0.0005

46 4 0.75

72 50

69 39

46 46 1.00

36 21 0.16

38 31 0.34

32 18 0.88

71 68

46 62

54 40 0.21

33 29 0.56

41 32 0.96

25 25 0.47

66 75

P

Treatment 60 Gy 65 Gy

3 years OS (%)

schedule

Ag$ < 75 yrs 2 75 yrs P

CR = complete remission;

OS = overall survival; CSS = cancer-specific

sion, the actuarial overall survival is 55% at 3 years and 33% at 5 years. The cancer-specific survival is 70% at 3 years and 60% at 5 years. Only nine patients in this group (18%) had a local recurrence as the only site of relapse. The actuarial local relapse free survival in the CR group is 7 1% at 3 years and 66% at 5 years. As previously reported and found by others (12, 18), tumor size was a striking influence on the chance to obtain a complete remission. Most complete remissions in our material were seen in patients with tumors less than 4 cm in diameter. Because all patients without a CR also failed locally, local control should remain the first treatment aim. Therefore, the overall CR rates of 46%, and of 52% in smaller (5 4 cm) tumors, are still disappointing. Several authors have shown that there is a dose-response relationship in lung cancer patients treated with radiotherapy (9, 13, 18-20). In Dosoretz et aZ.‘s series (3), the disease-free survival at 3 years for patients with tumors of less than 3 cm and treated with a dose higher than 65 Gy was 90%, which seems extremely good. Bearing this in mind, our doses of 60 and 65 Gy could be considered too low. Table 4. Our survival data and data from published Year

This series Zhang et al. (19) Sandler et al. (15) Talton et al. (17) Haffty et al. (7) Coy and Kennedy (3) Kaskovitz et al. (9) Dosoretz et al. (4)

survival; LRFS = local relapse-free

survival.

The RTOG dose escalation study (2) showed a dosesurvival relation only in patients with favorable characteristics. This supports our view that high dosages might only be beneficial for a selected subgroup of patients. Therefore, a logical step would be to increase the dose for the subset of patients with good prognostic factors. This, however, is only possible if the side effects of higher dosages can be kept within certain limits (19), especially because these patients usually have a poor pulmonary function. One way to do this is to irradiate small target volumes that encompass the primary tumor only. This approach is only justified if the patients’ outcomes were not negatively affected if the regional lymph nodes were not treated. In contrast to most studies on high-dose irradiation of medically inoperable lung cancer patients, regional lymph nodes were not irradiated in our patients. Of those who achieved local control, two (4%) relapsed in the regional lymph nodes as the only site. It could be argued that these two have missed their chance for a cure because the nodes were not treated. Overall 10 out of 108 (9%) had a locoregional relapse. series on curative radiotherapy

in lung cancer

1

2

3

4

5

Median

OSKSS

owcss

OSKSS

os/css

OSKSS

(months)

75/81 93/57157160 66l--

49158 36l31145 43/4013 1

OS = Overall survival (%); CSS = cancer-specific

survival (%).

31142 55l17/21/36/18133 19/-

20133 17/1405 lO/-

15/31 32l--I17 17/21/10/O 6llOI-

23 20 28 21 17

Local irradiation alone for lung cancer0 A. D. G.

If a higher local control rate could be obtained by a higher local dose, these patients would have missed their chance for a cure. All other patients also had distant metastases. Only when an improved local control would also reduce the distant me&stases rate, as suggested by Dorosetz ef al. (3), and not reduce the incidence of regional metastases, would the need for regional irradiation become more prominent. In patients with small centrally located tumors, irradiation of the hilum and (part of) the mediastinum seems to be necessary. Whether a high dose can also be given in these patients will depend on the location of the tumor and the pulmonary function of the patient. So far, however, it seems justified to limit the target volume to only the primary tumor in patients with small peripherally located tumors, creating the possibility of safely increasing the dose. CONCLUSION Although surgery is still the treatment of choice for resectable nonsmall cell cancer of the lung for the old age group, especially those with a poor pulmonary or cardiac condition, the immediate risk of death is not always outweighed by the improved results over radiotherapy claimed by surgery. Noordijk et al. (12) indicated, based on a matched control study and realizing the differences in stage (clinical or pathological), that

KROL

et al.

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the survival of patients of over 75 years of age, treated by local radiotherapy, was equal to the survival of those treated with surgery. The cancer-specific survival of patients in complete remission at 5 years of 60% in our series comes close to the survival rate after surgery. However, survival is not the best endpoint for the comparison of radiotherapy and surgery, because patients in both groups are differently staged (clinical vs. pathologic staging) and patients in the older age group also have a high risk of dying from noncancerrelated causes (30% in our series). Therefore, complete remission and persistent local control seems to be a more appropriate endpoint for judging the curative potential of radiotherapy. Although the local recurrence-free survival after complete remission in our series is encouraging, the complete remission rate leaves room for improvement. There is a suggestion that with higher dosages a higher CR rate and a higher recurrence-free survival could be obtained. Our data suggest that local irradiation only for peripherally located tumors, in patients with a poor pulmonary function, and without treating the regional lymph nodes, is justified due to the low regional recurrence rate. This observation creates the possibility for increasing the dose to the tumor, even with conformal therapy, without substantially increasing pulmonary toxicity due to the use of large locoregional target volumes.

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