Radiotherapy and Oncology, 20 (1991) 91-98 Elsevier
91
RADION 00797
Alternating radiotherapy and chemotherapy schedules in limited small cell lung cancer" analysis of local chest recurrences* R. A r r i a g a d a 1 B. P e l l a e - C o s s e t 1, j . C u e t o L a d r o n d e G u e v a r a 2, H . E1 B a k r y 3, F. B e n n a 1, M . M a r t i n 4, H . d e C r e m o u x 4, P. B a l d e y r o u 1, M . L. C e r r i n a 5 a n d T. L e C h e v a l i e r ~ Jlnstitut Gustave-Roussy, Villejuif, France, 2Hospital de Granada, Spain, 3Radiotherapy Department, National Institute of Cancer, From El Khalig, Cairo, Egypt, 4Centre Hospitalier Intercommunal de Cr~teil, France, and 5H6pital A. B~cl~re, Clamart, France
(Received 26 June 1989, revision received 27 April 1990, accepted 4 October 1990)
Key words': Small cell lung cancer; Combined radiotherapy and chemotherapy; Radiation technique; Local recurrence; Tumor dose
Summary An analysis of the chest recurrences was conducted in 72 consecutive patients with limited small cell lung cancer treated in two successive phase II trials alternating six induction chemotherapy courses and three series of thoracic radiotherapy, followed by maintenance chemotherapy. The total radiation dose was 45 Gy (3 series of 15 Gy) in the first trial, and 55 (20, 20 and 15 Gy) in the second. The effect of the irradiated volume was investigated by comparing the local relapse rates in the group of patients treated by radiation fields encompassing the initial tumor volume to another group in which the initial target volume was not fully covered by radiation fields. The definition of these two groups was performed retrospectively by examination of radiological, fiberoptic bronchoscopy initial findings, technical radiation charts and check films. The local recurrence rate were 33 and 36% in each group (no significant difference). This finding could suggest that tumor shrinkage after chemotherapy might allow the use of"reduced" radiation volumes. However, the limited number of patients does not permit a definite conclusion. The effect of radiation dose was investigated by comparing the local control rates in the two consecutive trials which delivered 45 and 55 Gy, respectively. No difference in long-term local control was found: the addition of 10 Gy in the second trial only seemed to delay the appearance of local recurrences by 6 months. Twenty percent of patients died from a local relapse without evidence of distant metastases. If the metastasis rate of 50% found in the whole series is assumed in this subset, 10% of patients could actually benefit from optimal local management. These findings stress the need to investigate more effective loco-regional therapies in limited small cell lung cancer.
Introduction Despite recent advances in the treatment of small cell lung cancer ( S C L C ) with intensive and aggressive treatment entailing chemotherapy and radiotherapy and despite 50-80~o [3,6,16,18,28,30] o f complete remissions (CR) obtained with combination of these two modalities in limited disease, local failure at the primary site continues to be as high as 40-60~o [3,6,16,28,30]. Some authors have proposed the hypothesis that local
failure might have an impact on patient survival [3,5,22,34]. Indeed, in our experience approximately 20 To o f patients do present with an isolated chest recurrence which leads to patient's death. An improvement in the tumor local control rate should therefore result in an improvement in the survival rate for this particular subset of patients. In 1980, we started protocols alternating radiotherapy and chemotherapy in limited S C L C with the aim o f improving both local control and survival rates.
Address for correspondence: R. Arriagada, Department of Radiotherapy, Institut Gustave-Roussy, rue Camille Desmoulins, 94805 Villejuif
Cedex, France * Presented at the 7th ESTRO meeting in The Hague, September 5-8, 1988. 0167-8140/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)
92 We performed an analysis on local chest recurrences in order to determine which therapeutic factors might be involved in these failures. Patients and methods
Seventy-two consecutive patients with limited histologically proven small cell lung cancer (SCLC) were included in this study. Twenty-eight patients were treated in a first protocol (031-002) from June 1980 to November 1981 and 44 in a second protocol (031-004) from December 1981 to July 1983. The minimal followup is 6 years and the mean follow-up is 78 months + 10. All these patients were treated at the Institut Gustave-Roussy (IGR) and cooperating centers. Radiotherapy was only given at the IGR and the Centre Hospitalier Intercommunal de Crrteil.
Patients and eligibility All patients had an histologically proven SCLC and were previously untreated. The performance status (Karnofsky's Index) was above 40. Patients were evaluated and staged by clinical examination, chest X-ray, blood count, chemistries, fiberoptic bronchoscopy, bone marrow biopsy, bone scan, liver CT scan or ultrasonography, brain scan or CT scan. The thoracic CT scan was not routinely performed at the beginning of this study. Patients with distant metastases were excluded; whereas patients with contralateral mediastinal, hilar or supraclavicular lymph node involvement or pleural effusion with negative histology and/or cytology were included.
three series of irradiation to the primary tumor, mediastinal and supraclavicular lymph nodes and prophylactic cranial irradiation (PCI) [ 1,17,18 ]. This was followed again by chemotherapy alternating with the second and third series of chest irradiation. All patients were restaged following the 6th course of chemotherapy. Patients in complete remission (CR), confirmed by fiberoptic bronchoscopy and negative histology, were given as maintenance chemotherapy two different alternating combinations for 12 cycles (031-002) and 8 cycles (031-004).
Chemotherapy (a) First protocol: Induction chemotherapy, doxorubicin 40 mg/m 2 in day 1; VP 16213 75 mg/m 2 day 1, 2, 3; methotrexate 400 mg/m 2 day 2 followed by folinic acid rescue; cyclophosphamide 300 mg/m 2 day 3-6. These were repeated every 4 weeks. The maintenance chemotherapy consisted of: doxorubicin 20 mg/m 2 day 1, 2; vincristine 1 mg/m 2 day 2; methotrexate 20 mg/m 2 day 3, 4. This was alternated with a second combination including VP 16213 100 mg/m 2 days 1, 2; cyclophosphamide 300 mg/m 2 days 3, 4, 5; procarbazine 100 mg/m 2 days 3, 10. The total duration of treatment was 18 months. (b) In the second protocol, methotrexate was replaced by cis-platinum 100 mg/m 2 day 2 in the induction regimen. The alternating maintenance chemotherapy was: (i) nitrogen mustard 5 mg/m 2 day i, vincristine i mg/m 2 day 2, methotrexate 20 mg/m 2 days 1, 2; and (ii) VP 16213 200 mg/m 2 days 1, 2: C C N U 25-50 mg/m 2 day 2; procarbazine 100 mg/m 2 day 3-10. The total duration of the treatment was 14 months.
Definitions of complete remission and of local recurrence Radiotherapy Complete remission (CR) was defined as complete disappearance of all objective tumor: (1) on the chest X-ray, (2) optically and histologically at the time of fiberoptic bronchoscopy, (3) without evidence of new disease. This restaging was identical to the initial one and was performed at the end of the induction treatment. Local recurrence was defined as any reappearance of tumor in the chest after CR. The recurrences were confirmed whenever possible by fiberoptic bronchoscopy and biopsy. We shall consider separately in-field relapses and "border recurrences" occurring at the edge of the radiation field.
Treatment Treatment was initiated with two courses of induction chemotherapy after which patients received the first of
Radiotherapy was given in three courses alternating with the chemotherapy cycles. In the first protocol, each course consisted of 15 Gy in 6 fractions over 10 days, using anterior and posterior portals. The target volume included all visible initial tumor with a 1-1.5 cm margin of normal lung tissue, mediastinum, both hilae and bilateral supraclavicular regions. Midline posterior spinal shielding was added in the third series in order to keep the spinal cord dose below 40 Gy and to reduce the dose to the esophagus. Eighteen MV photon energy was used in all patients except six for whom a cobalt v-ray beam was employed. In the second protocol the dose was increased to 20 Gy in the first and second course, delivering a total dose of 40 Gy by the anterior and posterior portals, the third course (15 Gy) was given by two lateral fields sparing the spinal cord. Twenty-one patients were treated by an
93 18 MV photon beam and a cobalt y-ray beam was used for 23 patients. All patients were given PCI at a dose of 30 Gy in 10 fractions over 12 days using two lateral fields during the first series of thoracic radiotherapy. Clinical findings. There were 65 men and 7 women. Mean age was 53.6 + 8.5 years (+ S.D.). The mean performance status as determined by the Karnofsky index was 81 + 12~o. Fifty-six patients presented with involved mediastinal nodes (N2) and six with supraclavicular nodes. Four percent of patients presented with T1, 47~o with T 2 and 4 9 ~ with T 3 tumors. Complete remission. 63 patients (87.5~o) achieved a complete remission after induction treatment, 24 (86 ~o) in the first protocol and 39 (88~o) in the second. 13
Study of local recurrence and technique of radiotherapy. Sixty-two patients (evaluation was impossible for one patient because of an incomplete technical chart) in CR were retrospectively studied from a technical point of view taking into account the clinical charts, the fiberoptic bronchoscopy report, the radiological documents, the simulator films, the treatment check films and the computer dosimetry. A 3-step procedure was adopted for each patient: (1) The limits of the initial tumor and involved mediastinal nodes were drawn by the pneumologist on the frontal and lateral chest films, taking into account clinical, fiberoptic bronchoscopic and radiological data. (2) This "target volume" was redrawn on the simulator films. We then determined whether or not the redefined initial tumor volume was fully encompassed by the radiation fields. (3) The final step, was an evaluation of the safety margin for the anterior-posterior and lateral fields (distance between the target volume and the border of the fields). When the safety margin was superior or equal to 1 cm, the portals were considered to be adequate. The portals were considered inadequate when the safety margin was less than 1 cm or when the fields clearly did not encompass the whole target volume. The inadequately treated surface of the target volume was estimated by multiplying the two diameters of the area (see Fig. i). Statistical analysis used the life table method, the logrank test and the Z 2 test to evaluate differences in the incidence of local recurrences.
Fig. 1. Evaluation of adequate or inadequate coverage. (A) The safety margin is equal to 1 cm, the portal was considered as adequate. (B) The portal did not encompass the whole target volume, the inadequately treated surface of the target volume was estimated by multiplying x and y.
Results
Overall results concerning these protocols have been previously published [ 1,17,18 ]. Briefly, the CR rate was 87~o and overall survival was 26~o at 3 years. Local recurrences. The actuarial local control rate for CR patients was 88, 64 and 52~o at 1, 2 and 5 years, respectively. Twenty-two local recurrences were observed: 9 in the first protocol and 13 in the second protocol. In 15 cases the local recurrence was the only site of relapse and led to the patient's death. Sixteen local recurrences (73 ~o) appeared in the radiation field and only six (27~/o) were "border recurrences". Most
94 100.
TABLE I
90,
Local recurrence (~o) and tumor coverage.
BO,
Adequate coverage
Inadequate coverage
P
70, 60~
All patients 33 (4/12) Protocol 002 33 (2/6) Protocol 004 33 (2/6)
36 (18/50) 41 (7/17) 33 (11/33)
0.86 0.74 1.00
50. 40 3O 20 10
recurrences occurred during the first 2 years of followup and only four local relapses were noted later.
0 0
" 6
. 12
I 16
' 24 •
' 30 =
' 36 =
' 42 .
' 48 =
' 54
' 60
.
=
Months
Local recurrences and target volume coverage. These results are shown in Table I. Fifty out of 62 patients had an inadequate coverage. This high percentage could be explained by the reluctance o f some radiotherapists to irradiate a very large lung volume when a significant decrease in tumor size had been obtained by chemotherapy. N o significant differences were observed between patients treated with adequate or inadequate coverage. Nine out of 18 patients presenting with a local recurrence and inadequate coverage, initially had pleural effusion or extended atelectasis. The detailed results o f the second protocol in which lateral fields were used are shown in Table II. Overall results take into account coverage by lateral fields; two cutpoints were used for the anterior-posterior fields: complete coverage and partial coverage, where 10 cm 2 of non-coverage was accepted as adequate coverage. Other subgroups could not be studied because of the small n u m b e r o f recurrences; there was no significant difference between adequate and inadequate coverage whatever the cutpoint used.
Fig. 2. Actuarial local control for complete responders in protocols 002 (continuous line) (total radiation dose: 45 Gy) and 004 (broken line) (total radiation dose: 55 Gy). There is no significant difference in long-term local control. The addition of 10 Gy only seems to delay the appearance of local recurrences up to 2 years of follow-up for a mean time of 6 months.
local relapse was 14 m o n t h s for protocol 002 and 20 m o n t h s for protocol 004 (p = 0.08).
100.]~-~ 90
5
80. 70. 60.
X
50. 40 30
20 16
20.
Local recurrences and radiation dose. Actuarial local control curves for protocols 031-002 (45 Gy) and 031-004 (55 G y ) are shown in Fig. 2. There is no significant difference between the two protocols at 5 years, but the higher dose protocol tends to delay local recurrence by 6 months. The mean time for the appearance o f a
10 0 0
; 6
12
~ 18
; 24
• 30
.. 36
; 42
; 48
: 54
; 60
Months
Fig. 3. Overall survival of CR patients. The 5-year survival is 26~o (C.I. 95~o : 16-39~).
TABLE II Local chest recurrences (~) according to different definitions of the tumor coverage (protocol 004). Adequate coverage
Inadequate coverage
p
All fields
33 (2/6)
33 (11/33)
1.00
Only AP fields Complete coverage Non-coverage < 10 cm2
20 (4/20) 30 (9/30)
47 (9/19) 44 (4/9)
0.14 0.42
95 TABLE III Intra-thoracic recurrences according to tumor coverage. Reference
Mantyla [20] Original tumor volume Reduced tumor volume Perez [29] Adequate portals Inadequate portals White [34] Fully evaluable or minor variations Major protocol variations Kies [16] Wide volume radiotherapy Reduced volume radiotherapy IGR Adequate coverage Inadequate coverage
n
Intrathoracic recurrence (~o)
p
28 24
18 58
0.003
40 13
33 69
0.02
38 16
34 69
0.04
93 98
32 28
N.S.
12 50
33 36
0.86
* Randomized trial in partial responders only.
Local recurrence and other prognostic factors. A multivariate analysis was performed in both protocols taking into account different prognostic factors. T 3 tumors versus T~ and T 2 showed a non-significant trend (p = 0.12) towards a higher rate of local recurrence. Overall survival of patients in complete remission (see Fig. 3). The survival rate at 5 years is 26 ~o in both protocols (p = 0.6). Discussion
Byhardt and Cox [4,5,9-11] have emphasized the importance of intrathoracic tumor control as a major survival determinant for the SCLC patients. Recently published randomized studies have demonstrated a significant benefit in combining thoracic radiotherapy with chemotherapy in terms of local control rate and 4 of them in terms of survival [ 3,14,16,28,30 ]. However, the optimal delivery of thoracic irradiation required remains a subject of debate. We will discuss mainly two questions: (1) What volume should be treated: the initial one or only the residual (post-chemotherapy) volume with a wide free margin?; (2) what dose of irradiation should be delivered?. In our series, we found that only 19~o (12/62) of patients had an adequate radiation field coverage when the target volume was retrospectively redefined by the pneumologist who had performed the initial fiberoptic bronchoscopy. This rate was 26~o (6/23) in the first protocol and 15~o (6/39) in the second one. Inadequate
coverage by the lateral portals was responsible for most target volume miss in the second protocol. When only the antero-posterior beams were taken into account the percentage of adequate coverage was 50 ~o (Table II). In spite of this high rate of inadequate coverage, the 2-year actuarial local recurrence rate was only 36~o, and there was no difference in local relapse rates in patients treated with adequate or inadequate coverage. On the other hand, some other published series, summarized in Table III, have shown a different effect. Perez et al. [29], in a study on technical factors and intrathoracic recurrences, observed a better local control rate in patients treated with adequate portals than in those treated with inadequate fields. However, what Perez considered as "inadequate" portals were clearly major protocol violations (uncovered contralateral hilum or mediastinal lymph nodes), which cannot be compared with the strict definition chosen in our study. White [34] also studied the impact of the quality of thoracic irradiation. He reported that radiation quality was a significant predictor of survival. However, again the inadequate portals were defined as "major protocol variations" apparently, to a much further extent than in our series. Similarly, in the non-randomized study of Mantyl~ [20] 14 relapses (58~o) were observed in 24 patients irradiated with reduced fields (post-chemotherapy volume) whereas only five relapses (18 ~o) were noted in 28 patients whose fields encompassed the initial tumor. In the Southwest Oncology Group trial, 207 patients in partial remission or with stable disease after induction chemotherapy were randomized to receive a chest irradiation covering either the pre- or the post-induction tumor volume. Out of the 191 eligible patients no difference has emerged in the local relapse rate [16]. However in a subsequent abstract [23], the same authors reported that in 48 cases with information regarding patterns of chest relapse, relapse outside the field was higher in the reduced-volume radiotherapy group: 65 ~o versus 16~o in the wide-volume radiotherapy group (p = 0.001). This last finding can be criticized as being merely a data-derived analysis, limited to a subgroup of patients. One of the probable factors favoring local recurrences is the presence of large pleural effusion or atelectasis that complicates the evaluation of the volume to be treated. For some authors [2,4] this would indicate that pre-chemotherapy radiation portal planning using the CT scan is necessary for accurate tumor coverage. CT scan was not systematically used in our series. However, even if the tumor volume can be correctly defined, a controversy persists about the amount of surrounding lung which should be treated after
96 chemotherapy. Our own data showed no increase in the local relapse rate even in the event of inadequate coverage of the initial tumor volume. This finding is corroborated by the overall results of the only randomized trial conducted on this topic [16]; this fact would suggest that tumor shrinkage after chemotherapy is sufficient to allow the tumor to be completely encompassed by "inadequate" fields. These results, however, are challenged by the retrospective data summarized in Table III. Two reasons can explain this contradiction: the difficulties involved defining what adequate coverage means and the relatively small number of patients analyzed. Furthermore, the most frequent site of relapse was inside the fields when the volume of irradiation encompassed the original tumor volume before chemotherapy. This possibly reflects an insufficient dose level [ 13,27,30]. Previous studies [ 9,17,21,24] investigated the radiation dose response relationship and suggested that the improvement of local control is proportional to the dose. Cox et al. [ 12] suggested a chemotherapy effect permitting a reduction in the dose of radiation. Nevertheless, in several studies combining chemotherapy and radiotherapy, the higher doses (45-50 Gy) were found to be more effective than lower doses (30-40 Gy) [7,8,15,32]. In an analysis of long-term survivors with SCLC, Peschel [31] noted that most of these patients had received a higher dose than 48 Gy. Papac [26] reported a 3.8 ~o thoracic relapse rate after a dose of 60 Gy but with quite a substantial pulmonary complication rate. The only randomized trial on radiation dose was conducted in Canada [13], but the dose levels compared were rather low and moderate: 25 Gy in 10 fractions over 2 weeks and 37.5 Gy in 15 fractions over 3 weeks, respectively. The authors concluded that the use of a "higher" dose seemed to delay rather than prevent thoracic recurrence. In the present study, the definitive local control was similar in both protocol delivering a total radiation dose of 45 Gy and 55 Gy. As in the Canadian experience, the higher dose seemed only to delay the appearance of local recurrence, but this statement can be challenged because of simultaneous change in the induction chemotherapy regimens. So, from retrospective data we can assume that
the optimal total dose could be in the range of 50-55 Gy, but the problem clearly needs further investigations because the upper range of doses has been poorly explored. Another important factor that can affect the adequacy of treatment is the timing of radiotherapy and chemotherapy, It has been suggested by Catane et al. [6] and Minna et al. [22], that concurrent treatment results in higher local control and survival rates than sequential treatment. However, concurrent combination may yield higher morbidity and mortality rates and necessitates careful planning and close patient care. The local effect of this type of treatment could be due to a minimizing of cell repopulation which might take place between the chemotherapy cycles. SCLC has been shown to exhibit a high labelling index [19,25]. This may explain the higher incidence of local failure with sequential treatment. In our protocols, the alternating radiotherapy and chemotherapy schedules attempt to benefit from the advantages of concurrent treatment along with the reduced toxicity observed in sequential schedules [33]. Another fact to be pointed out is the 2 0 ~ of our patients for whom death was only due to a local recurrence. In our series, the overall distant metastasis rate was 50~o [ 18]. If we assume that the same proportion of infraclinical dissemination exists in patients presenting with an apparently isolated local recurrence, complete local control could achieve a 10~ additional survival benefit. Since local control is still a problem in the management of limited SCLC, more detailed analyses and prospective studies on volume, radiation dose, and timing of chemotherapy and radiotherapy should be conducted. A theoretical 10 ~o of survival benefit could be achieved with optimal local management and this would be a considerable mid-term goal in limited SCLC.
Acknowledgements The authors would like to thank Mrs. M. Mousse, and L. Saint-Ange for their assistance in the preparation of this manuscript.
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98 31 Peschel, R. E., Kapp, D. S., Carter, D. and Knowlton, A. Long term survivors with small cell carcinoma of the lung. Int. J. Radiat. Oncol. Biol. Phys. 7: 1545-1548, 1981. 32 Souhami, R.L., Geddes, D.M., Spiro, S.G., Harper, P.G., Tobias, J. S., Mantell, B. S. K. and Bradbury, I. Radiotherapy in small cell cancer of the lung treated with combination chemotherapy: A controlled trial. Br. Med. J. 288: 1643-1646, 1984. 33 Tubiana, M., Arriagada, R. and Cosset, J.M. Sequencing of
drugs and radiation. The integrated alternating regimen. Cancer 55: 2131-2139, 1985. 34 White, J. E., Chen, T., MacCracken, J., Kennedy, P., Seydel, M. G., Hartman, G., Mira, J. Khan, J., Durrance, F.Y. and Skinner, O. The influence of radiation therapy quality control on survival, response and sites of relapse in oat cell carcinoma of the lung. Preliminary report of a Southwest Oncology Group Study. Cancer 50: 1084-1090, 1982.
91
RADION 00797
Alternating radiotherapy and chemotherapy schedules in limited small cell lung cancer" analysis of local chest recurrences* R. A r r i a g a d a 1 B. P e l l a e - C o s s e t 1, j . C u e t o L a d r o n d e G u e v a r a 2, H . E1 B a k r y 3, F. B e n n a 1, M . M a r t i n 4, H . d e C r e m o u x 4, P. B a l d e y r o u 1, M . L. C e r r i n a 5 a n d T. L e C h e v a l i e r ~ Jlnstitut Gustave-Roussy, Villejuif, France, 2Hospital de Granada, Spain, 3Radiotherapy Department, National Institute of Cancer, From El Khalig, Cairo, Egypt, 4Centre Hospitalier Intercommunal de Cr~teil, France, and 5H6pital A. B~cl~re, Clamart, France
(Received 26 June 1989, revision received 27 April 1990, accepted 4 October 1990)
Key words': Small cell lung cancer; Combined radiotherapy and chemotherapy; Radiation technique; Local recurrence; Tumor dose
Summary An analysis of the chest recurrences was conducted in 72 consecutive patients with limited small cell lung cancer treated in two successive phase II trials alternating six induction chemotherapy courses and three series of thoracic radiotherapy, followed by maintenance chemotherapy. The total radiation dose was 45 Gy (3 series of 15 Gy) in the first trial, and 55 (20, 20 and 15 Gy) in the second. The effect of the irradiated volume was investigated by comparing the local relapse rates in the group of patients treated by radiation fields encompassing the initial tumor volume to another group in which the initial target volume was not fully covered by radiation fields. The definition of these two groups was performed retrospectively by examination of radiological, fiberoptic bronchoscopy initial findings, technical radiation charts and check films. The local recurrence rate were 33 and 36% in each group (no significant difference). This finding could suggest that tumor shrinkage after chemotherapy might allow the use of"reduced" radiation volumes. However, the limited number of patients does not permit a definite conclusion. The effect of radiation dose was investigated by comparing the local control rates in the two consecutive trials which delivered 45 and 55 Gy, respectively. No difference in long-term local control was found: the addition of 10 Gy in the second trial only seemed to delay the appearance of local recurrences by 6 months. Twenty percent of patients died from a local relapse without evidence of distant metastases. If the metastasis rate of 50% found in the whole series is assumed in this subset, 10% of patients could actually benefit from optimal local management. These findings stress the need to investigate more effective loco-regional therapies in limited small cell lung cancer.
Introduction Despite recent advances in the treatment of small cell lung cancer ( S C L C ) with intensive and aggressive treatment entailing chemotherapy and radiotherapy and despite 50-80~o [3,6,16,18,28,30] o f complete remissions (CR) obtained with combination of these two modalities in limited disease, local failure at the primary site continues to be as high as 40-60~o [3,6,16,28,30]. Some authors have proposed the hypothesis that local
failure might have an impact on patient survival [3,5,22,34]. Indeed, in our experience approximately 20 To o f patients do present with an isolated chest recurrence which leads to patient's death. An improvement in the tumor local control rate should therefore result in an improvement in the survival rate for this particular subset of patients. In 1980, we started protocols alternating radiotherapy and chemotherapy in limited S C L C with the aim o f improving both local control and survival rates.
Address for correspondence: R. Arriagada, Department of Radiotherapy, Institut Gustave-Roussy, rue Camille Desmoulins, 94805 Villejuif
Cedex, France * Presented at the 7th ESTRO meeting in The Hague, September 5-8, 1988. 0167-8140/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)
92 We performed an analysis on local chest recurrences in order to determine which therapeutic factors might be involved in these failures. Patients and methods
Seventy-two consecutive patients with limited histologically proven small cell lung cancer (SCLC) were included in this study. Twenty-eight patients were treated in a first protocol (031-002) from June 1980 to November 1981 and 44 in a second protocol (031-004) from December 1981 to July 1983. The minimal followup is 6 years and the mean follow-up is 78 months + 10. All these patients were treated at the Institut Gustave-Roussy (IGR) and cooperating centers. Radiotherapy was only given at the IGR and the Centre Hospitalier Intercommunal de Crrteil.
Patients and eligibility All patients had an histologically proven SCLC and were previously untreated. The performance status (Karnofsky's Index) was above 40. Patients were evaluated and staged by clinical examination, chest X-ray, blood count, chemistries, fiberoptic bronchoscopy, bone marrow biopsy, bone scan, liver CT scan or ultrasonography, brain scan or CT scan. The thoracic CT scan was not routinely performed at the beginning of this study. Patients with distant metastases were excluded; whereas patients with contralateral mediastinal, hilar or supraclavicular lymph node involvement or pleural effusion with negative histology and/or cytology were included.
three series of irradiation to the primary tumor, mediastinal and supraclavicular lymph nodes and prophylactic cranial irradiation (PCI) [ 1,17,18 ]. This was followed again by chemotherapy alternating with the second and third series of chest irradiation. All patients were restaged following the 6th course of chemotherapy. Patients in complete remission (CR), confirmed by fiberoptic bronchoscopy and negative histology, were given as maintenance chemotherapy two different alternating combinations for 12 cycles (031-002) and 8 cycles (031-004).
Chemotherapy (a) First protocol: Induction chemotherapy, doxorubicin 40 mg/m 2 in day 1; VP 16213 75 mg/m 2 day 1, 2, 3; methotrexate 400 mg/m 2 day 2 followed by folinic acid rescue; cyclophosphamide 300 mg/m 2 day 3-6. These were repeated every 4 weeks. The maintenance chemotherapy consisted of: doxorubicin 20 mg/m 2 day 1, 2; vincristine 1 mg/m 2 day 2; methotrexate 20 mg/m 2 day 3, 4. This was alternated with a second combination including VP 16213 100 mg/m 2 days 1, 2; cyclophosphamide 300 mg/m 2 days 3, 4, 5; procarbazine 100 mg/m 2 days 3, 10. The total duration of treatment was 18 months. (b) In the second protocol, methotrexate was replaced by cis-platinum 100 mg/m 2 day 2 in the induction regimen. The alternating maintenance chemotherapy was: (i) nitrogen mustard 5 mg/m 2 day i, vincristine i mg/m 2 day 2, methotrexate 20 mg/m 2 days 1, 2; and (ii) VP 16213 200 mg/m 2 days 1, 2: C C N U 25-50 mg/m 2 day 2; procarbazine 100 mg/m 2 day 3-10. The total duration of the treatment was 14 months.
Definitions of complete remission and of local recurrence Radiotherapy Complete remission (CR) was defined as complete disappearance of all objective tumor: (1) on the chest X-ray, (2) optically and histologically at the time of fiberoptic bronchoscopy, (3) without evidence of new disease. This restaging was identical to the initial one and was performed at the end of the induction treatment. Local recurrence was defined as any reappearance of tumor in the chest after CR. The recurrences were confirmed whenever possible by fiberoptic bronchoscopy and biopsy. We shall consider separately in-field relapses and "border recurrences" occurring at the edge of the radiation field.
Treatment Treatment was initiated with two courses of induction chemotherapy after which patients received the first of
Radiotherapy was given in three courses alternating with the chemotherapy cycles. In the first protocol, each course consisted of 15 Gy in 6 fractions over 10 days, using anterior and posterior portals. The target volume included all visible initial tumor with a 1-1.5 cm margin of normal lung tissue, mediastinum, both hilae and bilateral supraclavicular regions. Midline posterior spinal shielding was added in the third series in order to keep the spinal cord dose below 40 Gy and to reduce the dose to the esophagus. Eighteen MV photon energy was used in all patients except six for whom a cobalt v-ray beam was employed. In the second protocol the dose was increased to 20 Gy in the first and second course, delivering a total dose of 40 Gy by the anterior and posterior portals, the third course (15 Gy) was given by two lateral fields sparing the spinal cord. Twenty-one patients were treated by an
93 18 MV photon beam and a cobalt y-ray beam was used for 23 patients. All patients were given PCI at a dose of 30 Gy in 10 fractions over 12 days using two lateral fields during the first series of thoracic radiotherapy. Clinical findings. There were 65 men and 7 women. Mean age was 53.6 + 8.5 years (+ S.D.). The mean performance status as determined by the Karnofsky index was 81 + 12~o. Fifty-six patients presented with involved mediastinal nodes (N2) and six with supraclavicular nodes. Four percent of patients presented with T1, 47~o with T 2 and 4 9 ~ with T 3 tumors. Complete remission. 63 patients (87.5~o) achieved a complete remission after induction treatment, 24 (86 ~o) in the first protocol and 39 (88~o) in the second. 13
Study of local recurrence and technique of radiotherapy. Sixty-two patients (evaluation was impossible for one patient because of an incomplete technical chart) in CR were retrospectively studied from a technical point of view taking into account the clinical charts, the fiberoptic bronchoscopy report, the radiological documents, the simulator films, the treatment check films and the computer dosimetry. A 3-step procedure was adopted for each patient: (1) The limits of the initial tumor and involved mediastinal nodes were drawn by the pneumologist on the frontal and lateral chest films, taking into account clinical, fiberoptic bronchoscopic and radiological data. (2) This "target volume" was redrawn on the simulator films. We then determined whether or not the redefined initial tumor volume was fully encompassed by the radiation fields. (3) The final step, was an evaluation of the safety margin for the anterior-posterior and lateral fields (distance between the target volume and the border of the fields). When the safety margin was superior or equal to 1 cm, the portals were considered to be adequate. The portals were considered inadequate when the safety margin was less than 1 cm or when the fields clearly did not encompass the whole target volume. The inadequately treated surface of the target volume was estimated by multiplying the two diameters of the area (see Fig. i). Statistical analysis used the life table method, the logrank test and the Z 2 test to evaluate differences in the incidence of local recurrences.
Fig. 1. Evaluation of adequate or inadequate coverage. (A) The safety margin is equal to 1 cm, the portal was considered as adequate. (B) The portal did not encompass the whole target volume, the inadequately treated surface of the target volume was estimated by multiplying x and y.
Results
Overall results concerning these protocols have been previously published [ 1,17,18 ]. Briefly, the CR rate was 87~o and overall survival was 26~o at 3 years. Local recurrences. The actuarial local control rate for CR patients was 88, 64 and 52~o at 1, 2 and 5 years, respectively. Twenty-two local recurrences were observed: 9 in the first protocol and 13 in the second protocol. In 15 cases the local recurrence was the only site of relapse and led to the patient's death. Sixteen local recurrences (73 ~o) appeared in the radiation field and only six (27~/o) were "border recurrences". Most
94 100.
TABLE I
90,
Local recurrence (~o) and tumor coverage.
BO,
Adequate coverage
Inadequate coverage
P
70, 60~
All patients 33 (4/12) Protocol 002 33 (2/6) Protocol 004 33 (2/6)
36 (18/50) 41 (7/17) 33 (11/33)
0.86 0.74 1.00
50. 40 3O 20 10
recurrences occurred during the first 2 years of followup and only four local relapses were noted later.
0 0
" 6
. 12
I 16
' 24 •
' 30 =
' 36 =
' 42 .
' 48 =
' 54
' 60
.
=
Months
Local recurrences and target volume coverage. These results are shown in Table I. Fifty out of 62 patients had an inadequate coverage. This high percentage could be explained by the reluctance o f some radiotherapists to irradiate a very large lung volume when a significant decrease in tumor size had been obtained by chemotherapy. N o significant differences were observed between patients treated with adequate or inadequate coverage. Nine out of 18 patients presenting with a local recurrence and inadequate coverage, initially had pleural effusion or extended atelectasis. The detailed results o f the second protocol in which lateral fields were used are shown in Table II. Overall results take into account coverage by lateral fields; two cutpoints were used for the anterior-posterior fields: complete coverage and partial coverage, where 10 cm 2 of non-coverage was accepted as adequate coverage. Other subgroups could not be studied because of the small n u m b e r o f recurrences; there was no significant difference between adequate and inadequate coverage whatever the cutpoint used.
Fig. 2. Actuarial local control for complete responders in protocols 002 (continuous line) (total radiation dose: 45 Gy) and 004 (broken line) (total radiation dose: 55 Gy). There is no significant difference in long-term local control. The addition of 10 Gy only seems to delay the appearance of local recurrences up to 2 years of follow-up for a mean time of 6 months.
local relapse was 14 m o n t h s for protocol 002 and 20 m o n t h s for protocol 004 (p = 0.08).
100.]~-~ 90
5
80. 70. 60.
X
50. 40 30
20 16
20.
Local recurrences and radiation dose. Actuarial local control curves for protocols 031-002 (45 Gy) and 031-004 (55 G y ) are shown in Fig. 2. There is no significant difference between the two protocols at 5 years, but the higher dose protocol tends to delay local recurrence by 6 months. The mean time for the appearance o f a
10 0 0
; 6
12
~ 18
; 24
• 30
.. 36
; 42
; 48
: 54
; 60
Months
Fig. 3. Overall survival of CR patients. The 5-year survival is 26~o (C.I. 95~o : 16-39~).
TABLE II Local chest recurrences (~) according to different definitions of the tumor coverage (protocol 004). Adequate coverage
Inadequate coverage
p
All fields
33 (2/6)
33 (11/33)
1.00
Only AP fields Complete coverage Non-coverage < 10 cm2
20 (4/20) 30 (9/30)
47 (9/19) 44 (4/9)
0.14 0.42
95 TABLE III Intra-thoracic recurrences according to tumor coverage. Reference
Mantyla [20] Original tumor volume Reduced tumor volume Perez [29] Adequate portals Inadequate portals White [34] Fully evaluable or minor variations Major protocol variations Kies [16] Wide volume radiotherapy Reduced volume radiotherapy IGR Adequate coverage Inadequate coverage
n
Intrathoracic recurrence (~o)
p
28 24
18 58
0.003
40 13
33 69
0.02
38 16
34 69
0.04
93 98
32 28
N.S.
12 50
33 36
0.86
* Randomized trial in partial responders only.
Local recurrence and other prognostic factors. A multivariate analysis was performed in both protocols taking into account different prognostic factors. T 3 tumors versus T~ and T 2 showed a non-significant trend (p = 0.12) towards a higher rate of local recurrence. Overall survival of patients in complete remission (see Fig. 3). The survival rate at 5 years is 26 ~o in both protocols (p = 0.6). Discussion
Byhardt and Cox [4,5,9-11] have emphasized the importance of intrathoracic tumor control as a major survival determinant for the SCLC patients. Recently published randomized studies have demonstrated a significant benefit in combining thoracic radiotherapy with chemotherapy in terms of local control rate and 4 of them in terms of survival [ 3,14,16,28,30 ]. However, the optimal delivery of thoracic irradiation required remains a subject of debate. We will discuss mainly two questions: (1) What volume should be treated: the initial one or only the residual (post-chemotherapy) volume with a wide free margin?; (2) what dose of irradiation should be delivered?. In our series, we found that only 19~o (12/62) of patients had an adequate radiation field coverage when the target volume was retrospectively redefined by the pneumologist who had performed the initial fiberoptic bronchoscopy. This rate was 26~o (6/23) in the first protocol and 15~o (6/39) in the second one. Inadequate
coverage by the lateral portals was responsible for most target volume miss in the second protocol. When only the antero-posterior beams were taken into account the percentage of adequate coverage was 50 ~o (Table II). In spite of this high rate of inadequate coverage, the 2-year actuarial local recurrence rate was only 36~o, and there was no difference in local relapse rates in patients treated with adequate or inadequate coverage. On the other hand, some other published series, summarized in Table III, have shown a different effect. Perez et al. [29], in a study on technical factors and intrathoracic recurrences, observed a better local control rate in patients treated with adequate portals than in those treated with inadequate fields. However, what Perez considered as "inadequate" portals were clearly major protocol violations (uncovered contralateral hilum or mediastinal lymph nodes), which cannot be compared with the strict definition chosen in our study. White [34] also studied the impact of the quality of thoracic irradiation. He reported that radiation quality was a significant predictor of survival. However, again the inadequate portals were defined as "major protocol variations" apparently, to a much further extent than in our series. Similarly, in the non-randomized study of Mantyl~ [20] 14 relapses (58~o) were observed in 24 patients irradiated with reduced fields (post-chemotherapy volume) whereas only five relapses (18 ~o) were noted in 28 patients whose fields encompassed the initial tumor. In the Southwest Oncology Group trial, 207 patients in partial remission or with stable disease after induction chemotherapy were randomized to receive a chest irradiation covering either the pre- or the post-induction tumor volume. Out of the 191 eligible patients no difference has emerged in the local relapse rate [16]. However in a subsequent abstract [23], the same authors reported that in 48 cases with information regarding patterns of chest relapse, relapse outside the field was higher in the reduced-volume radiotherapy group: 65 ~o versus 16~o in the wide-volume radiotherapy group (p = 0.001). This last finding can be criticized as being merely a data-derived analysis, limited to a subgroup of patients. One of the probable factors favoring local recurrences is the presence of large pleural effusion or atelectasis that complicates the evaluation of the volume to be treated. For some authors [2,4] this would indicate that pre-chemotherapy radiation portal planning using the CT scan is necessary for accurate tumor coverage. CT scan was not systematically used in our series. However, even if the tumor volume can be correctly defined, a controversy persists about the amount of surrounding lung which should be treated after
96 chemotherapy. Our own data showed no increase in the local relapse rate even in the event of inadequate coverage of the initial tumor volume. This finding is corroborated by the overall results of the only randomized trial conducted on this topic [16]; this fact would suggest that tumor shrinkage after chemotherapy is sufficient to allow the tumor to be completely encompassed by "inadequate" fields. These results, however, are challenged by the retrospective data summarized in Table III. Two reasons can explain this contradiction: the difficulties involved defining what adequate coverage means and the relatively small number of patients analyzed. Furthermore, the most frequent site of relapse was inside the fields when the volume of irradiation encompassed the original tumor volume before chemotherapy. This possibly reflects an insufficient dose level [ 13,27,30]. Previous studies [ 9,17,21,24] investigated the radiation dose response relationship and suggested that the improvement of local control is proportional to the dose. Cox et al. [ 12] suggested a chemotherapy effect permitting a reduction in the dose of radiation. Nevertheless, in several studies combining chemotherapy and radiotherapy, the higher doses (45-50 Gy) were found to be more effective than lower doses (30-40 Gy) [7,8,15,32]. In an analysis of long-term survivors with SCLC, Peschel [31] noted that most of these patients had received a higher dose than 48 Gy. Papac [26] reported a 3.8 ~o thoracic relapse rate after a dose of 60 Gy but with quite a substantial pulmonary complication rate. The only randomized trial on radiation dose was conducted in Canada [13], but the dose levels compared were rather low and moderate: 25 Gy in 10 fractions over 2 weeks and 37.5 Gy in 15 fractions over 3 weeks, respectively. The authors concluded that the use of a "higher" dose seemed to delay rather than prevent thoracic recurrence. In the present study, the definitive local control was similar in both protocol delivering a total radiation dose of 45 Gy and 55 Gy. As in the Canadian experience, the higher dose seemed only to delay the appearance of local recurrence, but this statement can be challenged because of simultaneous change in the induction chemotherapy regimens. So, from retrospective data we can assume that
the optimal total dose could be in the range of 50-55 Gy, but the problem clearly needs further investigations because the upper range of doses has been poorly explored. Another important factor that can affect the adequacy of treatment is the timing of radiotherapy and chemotherapy, It has been suggested by Catane et al. [6] and Minna et al. [22], that concurrent treatment results in higher local control and survival rates than sequential treatment. However, concurrent combination may yield higher morbidity and mortality rates and necessitates careful planning and close patient care. The local effect of this type of treatment could be due to a minimizing of cell repopulation which might take place between the chemotherapy cycles. SCLC has been shown to exhibit a high labelling index [19,25]. This may explain the higher incidence of local failure with sequential treatment. In our protocols, the alternating radiotherapy and chemotherapy schedules attempt to benefit from the advantages of concurrent treatment along with the reduced toxicity observed in sequential schedules [33]. Another fact to be pointed out is the 2 0 ~ of our patients for whom death was only due to a local recurrence. In our series, the overall distant metastasis rate was 50~o [ 18]. If we assume that the same proportion of infraclinical dissemination exists in patients presenting with an apparently isolated local recurrence, complete local control could achieve a 10~ additional survival benefit. Since local control is still a problem in the management of limited SCLC, more detailed analyses and prospective studies on volume, radiation dose, and timing of chemotherapy and radiotherapy should be conducted. A theoretical 10 ~o of survival benefit could be achieved with optimal local management and this would be a considerable mid-term goal in limited SCLC.
Acknowledgements The authors would like to thank Mrs. M. Mousse, and L. Saint-Ange for their assistance in the preparation of this manuscript.
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