Im. J. RadiarionOncology Bid Phys., Vol. 18, pp. 1143-I I50 Printed in the U.S.A. All rights reserved.
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0360-3016/90 $3.00 + .oO 8 1990 Pergamon Press plc
??Phase I/II Clinical Trial
INTRAOPERATIVE RADIATION THERAPY COMBINED WITH EXTERNAL IRRADIATION IN NONRESECTABLE NON-SMALL-CELL LUNG CANCER: PRELIMINARY REPORT F. M. JUETTNER, J. SMOLLE,
M.D.,* K. ARIAN-SCHAD, M.D.,+ G. PORSCH, M.D.,+ H. LEITNER, PH.D.,+ M.D.,* F. EBNER, M.D.,’ A.HACKL, M.D.+ AND G. FRIEHS, M.D.* University Medical School of Graz, Austria
Twenty-one patients with nonresectable non-small-cell lung cancer (15 squamous-cell, 4 adeno, 2 large-cell; TlT3, NO-N2, all MO) underwent lymph node dissection and intraoperative irradiation of the tumor (IORT) with doses between 10 and 20 Gy (energies: 7 to 20 MeV electron beam). Postoperatively, 46-56 Gy external beam irradiation (8 or 23 MeV photon beam) were delivered to the mediastinum and 46 Gy to the tumor bearirrg area. Fifteen patients were available for follow-up investigations. The CT-scan tumor volumetry 4 weeks postoperatively showed a significant overall decrease (Wilcoxon test: p < 0.05) with eight minor responses (MR) (tumor regressions between 4 and 45%) and six partial responses (PR) (between 50 and 84%). One case was not evaluable. A second volumetry after external irradiation was done in 14 patients, 18 weeks after IORT, showing 3 complete responses, 10 partial responses (62 to 84%), and 1 minor response (28%). The recent volumetries (10 patients) between 4.5 and 16.5 months after IORT showed 7 complete responses and 3 partial responses (63 to 94%). One patient died from intrabronchial hemorrhage at 7 weeks. Three others died from unrelated causes, 6, 12 and 14 months, respectively, after IORT and in one further case the cause of death at 15 months was local tumor regrowth. Within the median time elapsed since IORT (12 months) only this one case of local regrowth and one further case of distant spread were observed. Lung cancer, Intraoperative radiation therapy, External beam irradiation, Response.
INTRODUCTION
Applied with both palliative and curative intent, the method has shown beneficial effects in a variety of tumors such as pancreatic, biliary, gastric, rectal, prostatic, and cerebral cancers as well as in sarcomas ( 1, 13). In non-small-cell lung cancer (NSCLC), surgery still offers the best chance of cure (5, 1 I), but there is a large number of patients whose tumors are nonresectable for anatomical or functional reasons. In some of these cases IORT might be indicated. Reports exist regarding a total of 59 patients with NSCLC, treated by megavoltage IORT (2, 3, 4, 13, 17’) but only in 13 of them are detailed data about the outcome given (3, 13, 17). Patient selection criteria, surgical treatment, and the radiotherapeutical schedule differed greatly
With intraoperative radiation therapy (IORT) using orthoor megavoltage teletherapy techniques, a single dose of ionizing radiation is delivered directly to the tumor or to the tumor bed at the time of operation (1). As otherwise dose limiting normal tissue can be protected from the beam by physical removal from the treatment field, meticulous focussing, or shielding techniques, the extent of normal tissue irradiation is minimized. This allows the delivery of large doses which can actually achieve control of the tumor. The low degree of collateral damage furthermore enables the use of IORT in combination with resection or external teletherapy (3, 13).
* Dept. Thoracic and Hyperbaric Surgery. + Dept. of Radiotherapy. Part of this paper was presented at the Second International Symposium on Intraoperative Radiation Therapy, Sept. 11- 14, 1988 Innsbruck, Austria, and at the UICC-Workshop on Progress in Regional Cancer Therapy, Nov. 3-5, 1988 Vienna, Austria.
Reprint requests to: F. M. Juettner, M.D., Dept. Thoracic and Hyperbaric Surgery, University Medical School of Graz, A8036 Graz, Austria. Accepted for publication 16 November 1989.
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even within one study, not enabling an objective evaluation of the results. Data about tumor regression are not available from any study. We conducted a controlled Phase I study on IORT and additional postoperative external beam irradiation of the tumor and of the mediastinal drainage area in nonresectable NSCLC. The aim of the study was to determine both the rate and the degree of local tumor response by objective criteria.
METHODS
AND MATERIALS
Since October 1987, we have treated 21 patients with NSCLC (19 males, 2 females; mean age: 65 years, range: 5 l-80; see Table 1). None of these patients could have tolerated radical surgery for lung cancer. During the operation it was discovered that 6 out of the 2 1 patients were nonresectable for anatomical reasons as well. Informed consent was obtained from all patients. Pre-operative evaluation Posterior-anterior and lateral chest roentgenograms, CT-scan, and fibrebronchoscopy were done to determine both type and local extent of the lesion. If no histological diagnosis could be obtained, a fine-needle aspiration cytology was performed. Distant metastases were ruled out by bone-scan and by hepatic sonography. Functional capacity was assessed by cardiopulmonary function tests (spirometry, body-plethysmography, exercise electrocardiogram, ultrasound cardiography, and ventilation-perfusion scan). The detailed causes of nonresectability are listed in Table 1. Surgery Surgery was done inside the radiation therapy room, which is completely equipped as an operating theater. The tumor bearing area was exposed by a posterolateral thoracotomy. In lesions the diagnosis of which had been established cytologically, a specimen for intraoperative frozen section histology was obtained by pulmotomy. The pulmotomy was closed by using absorbable sutures to diminish artefacts from suture material in the follow-up CT-scans. Dissection of Nl and N2-nodes was done in the respective drainage area. In cases 12 and 17 no lymph node dissection was performed, as the nodes had been removed during a preceding intervention. In cases 5, 6, 7, 19,20 infiltration of nodes into the bifurcation did not allow a radical dissection (for localization and pathological tumor stages see Table 1; the stage grouping was done according to the AJC criteria, 1979).
* Satume 25, dual photon therapy, 4, 7, 11, 15, 20, 25 MeV scanning electron beam; manufacturer: Generalelectrics, SGR, France.
May 1990, Volume 18. Number 5
IOR T A linear accelerator* with 4, 7, 11, 15-20, and 25 MeV electron energies was used. The accelerator beam was routinely calibrated every day. This enabled a prospective calculation of dosimetry data for all cone diameters and available energies. The data were listed in tables facilitating a quick determination of the irradiation parameters during irradiation. The choice of the optimal radiation energy and cone diameter in each individual case was based both on preand intraoperative findings. Doses from 10 to 20 Gy at energies from 7 to 20 MeV were delivered at the 90% isodose line (for the individual data see Table 2). Doses less than 20 Gy were only applied, if, due to anatomical reasons, a fully satisfactory protection of the adjacent organs was not possible. Self-manufactured Lucite cones with diameters from 6 to 10 cm were used for the treatment procedure. The cone was firmly put over the tumor and connected to the accelerator by a ring-shaped springsuspended diaphragm, providing a smooth docking. An inner aluminum ring of appropriate size was fitted into the diaphragm to constitute a secondary collimation and reduce lateral electron scatter at the cone wall (15). The direction of the beam was predetermined in a way that provided optimal protection of radiosensitive organs. If anatomically possible, further shielding was achieved with 40 mm thick aluminum sheets or 15 mm thick lead sheets, respectively, inserted between the tumor bearing lung and the underlying tissue. In 12 out of the 2 1 patients, IORT had to be done with both lungs ventilated due to functional reasons. In these cases, absorbable mattress sutures were used to pull the tumor-bearing area into the cone to prevent dislocation. In cases 5, 6, 7, 19, and 20 the incompletely dissected subcarinal lymph nodes were included into the port as far as possible. In Patient 20 infiltrating nodes at the hilum were irradiated separately using a second IORT port. During irradiation, the vital functions were monitored by ECG, continuous arterial blood pressure measurement, and capillary pulse-oxymetry, each of which was displayed outside the radiation therapy room. External irradiation 4 weeks after IORT the patients were scheduled for external beam irradiation on an outpatient basis. The portals were determined by using a simulator and a CTplanning system. Individually manufactured divergent cerrobend blocks were used to deliver a total dose of 46 Gy to the mediastinal lymph nodes and to the primary tumor. In Nl or N2 cases the dose to the mediastinum was increased up to 56 Gy. Either 8 or 23 meVp photon beams were applied, using AP/PA portals with additional
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IORT in lung cancer, local control 0 F. M. JUETTNER et al. Table 1. Pretreatment
No.
Aeetsex
Localization
TNM stage
-
data of nonresectable
Histoloav/aradina
1
68/m
1uL
T2NOMO
Squamous/G3
2
51/m
r1L
T 1NOMO
Squamous/G3
3
68/m
rlL
T2NlMO
Squamous/G2
4
73/f
1IL
T2NOMO
Adeno/GZ
5
74/m
1lL
T2N2MO
Squamous/G3
6
80/m
1uL
T3N2MO
AdenofG2
I
61/m
11L
T3N2MO
Squamous/G3
8
63/m
IUL
TlN2MO
Squamous/G3
9
61/m
IUL
T2NOMO
Squamous/G2
10
66/m
rlL
T2NOMO
Squamous/G3
11
57/m
ruL
TlNOMO
Adeno/GZ
12
65/f
1uL
TINOMO
Large cell/G2
13
73/m
11L
TlNOMO
Adeno/G3
14
70/m
ruL
T3NOMO
Squamous/G2
15
61/m
IUL
T3NOMO
Squamous/G2
16
55/m
rlL
T3N2MO
Adeno/G2
17
63/m
IIL
T 1NOM0
Squamous/G2
18
71/m
ruL
T2NlMO
Adeno/GZ
19
63/m
ruL
T3N2MO
Large cell/G2
20
57/m
1uL
T2N2MO
Squamous/G3
21
55/m
rlL
T3NOMO
Squamous/G3
NSCLC
Cause of unresectability Severe bullous emphysema, transitory ischemic attacks 3 and 5 years ago Cardiac insufficiency. coronary heart disease, severe bullous emphysema Coronary heart disease, bifascicular bloc (pacemaker), hypertension, diabetes melhtus, COLD Coronary heart disease. therapy resistant hypertension, diabetes mellitus COLD, hypertension. cardiac insufficiency N2infiltration into the bifurcation COLD, right ventricular strain, cerebrovascular insufficiency, tumor infiltration into the main pulmonary artery Therapy resistant arrhythmia (Lown 4b), COLD, N2-infiltration into the bifurcation Aortocoronary bypass-obstruction, stenocardia, posterior wall akinesia Cystectomy for bladder cancer T3NOG2; 1982 occlusion of the right iliac artery, bilateral occlusions of crural arteries. COLD Bilateral occlusion of iliac artery, bullous emphysema Myocardial infarction 3 months ago, 60% stenosis of interventricular branch of the left coronary artery (NYHA II; no dilation possible), extrasystoles (Lown IIIb) Myocardial infarction 8 years ago, wedgeresection of lung cancer ( 1uL) 3 years ago COLD, dyspnoea on exertion Cardiac insufficiency, COLD, history of cardiac asthma, dyspnoea on exertion Trifascicular block (pacemaker), coronary heart disease (NYHA II). atheroscleosis Dilatative cardiomyopathy. right ventricular strain, severe obstructive lung disease, diabetes mellitus Severe bullous emphysema, atherosclerosis right ventricular strain Ru-lobectomy 1982, wedge resection of r 1L 1987 both for squamous cell carcinoma, due to COLD no further resection Severe bullous emphysema, hypertensive car diomyopathy. coronary heart disease (NYHA II), dyspnoea on exertion 3 myocardial infarctions in history (no dilation or surgery possible, NYHA III) combined ventilation disorder Combined ventilation disorder, right ventricular strain, schizophrenia Severe obstructive lung disease
r = right; 1 = left: L = lobe.
lateral fields if indicated. 5 times a week.
The fractionation
was 2 Gy/day,
Folio w- up The first post-therapeutic CT-scan was done 4 weeks after IORT, followed by another CT-scan after the external
irradiation series 18 weeks after IORT. Further follow-up included monthly physical examinations and routine chest-roentgenograms as well as CT-scans of the chest and routine blood chemistry every 3 months. Bone-scans, hepatic sonography, and pulmonary function tests were performed at half yearly intervals.
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Table 2. Technical data of irradiation
Pt. no
Tumor diameter (max)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
6 2.5 4 3.5 7 8 6 3 3 3 3 4 3 6 8 5.5 3 4 9.5 3.5
21
7.5 cm
cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm
IORT tumor dose maximum/ radiation energy
Source-surface distance
Cone diameter
20 Gyf20 MeV 10 Gy/ll MeV 15 Gy/20 MeV 15 Gy/15 MeV 17 Gy/15 MeV 20 Gy/15 MeV 20 Gy/l 1 MeV 20 Gy/l5 MeV 20 Gyf20 MeV 20 Gy/ 15 MeV 20 Gy/l 1 MeV 20 Gyf 15 MeV 20 Gy/l 1 MeV 20 Gyj 15 MeV 20 Gy/ 15 MeV 20 Gy/20 MeV 20 Gy/15 MeV 20 Gyf 15 MeV 20 Gy/ 15 MeV 20 Gy/7 MeV 20 Gy/15 MeV 20 Gy/ 15 MeV
100 cm 100 cm 100 cm 91 cm 95 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 97 cm 100 cm 100 cm
8 cm 6 cm 8 cm 6cm 10 cm 10 cm 8 cm 6 cm 6 cm 8 cm 6cm 6 cm 6cm 8 cm 10 cm 6 cm 6 cm 6 cm 10 cm 4cm 8 cm (hilar port) 8 cm
External beam irradiation tumor 46 46 46 46 46 26 28 46 46 46 46 46 46 46 46
Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy
Note: In case 6 the external irradiation had to be discontinued for side-effects; in case 7, lethal intrabronchial Doses are calculated at the 90% isodose line. Patients 16-2 1 did not undergo external irradiation.
The assessment of primary tumor regression was based upon volumetry on CT-scans. The radiologist carrying out the measurements was not informed about the therapeutic modalities applied in the respective cases. For the whole group of patients, volumetric pre-treatment and post-treatment values 4 and 18 weeks postoperatively were evaluated by the non-parametric Wilcoxon matched pairs signed rank test. RESULTS
One patient died from unrelated causes 26 days after IORT. Three cases were lost to follow-up and two are still undergoing external beam irradiation. Fifteen patients were available for follow-up investigations. The IORT procedure was well tolerated. Thirteen out of the 15 patients were discharged 1 week after IORT. In case 1 a prolonged bronchopleural fistula due to severe bullous emphysema required intercostal suction drainage for 10 days. In Patient 6, a postoperative hospital stay of 17 days was necessary due to cerebrovascular insufficiency. During the second half of the external irradiation series all patients experienced more or less pronounced sideeffects from radiation treatment which in case 6 caused the treatment to be discontinued after 26 Gy. One patient (7) died from intrabronchial hemorrhage after 28 Gy. Generally, the patients were able to resume their normal life within 1 to 2 months alter the external treatment series.
External beam irradiation mediastinum 46 46 56 56 56 26 28 56 46 46 46 46 46 46 46
Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy
bleeding occurred.
So far, we have been unable to detect any side effects of IORT on the mediastinal viscera, peripheral nerves, or spinal cord. Three patients (1, 3, and 6) died 14, 12, and 6 months, respectively, after IORT due to causes unrelated to the tumor. One patient (5) died at 15 months due to local regrowth of lung cancer. Considering the whole group, tumor volume revealed a significant decrease 4 weeks postoperatively and again 18 weeks postoperatively (Wilcoxon matched pairs test: p < 0.05). The first postoperative evaluation of response by CTscan, 4 weeks after IORT, showed tumor regression in 14 out of the 15 patients: eight cases presented minor responses with a reduction of tumor volume between 4% and 45% (Fig. l), and six patients were found to have partial responses with a tumor shrinkage between 50 and 84%. In case 4 the lesion had increased to 127% of the initial volume (see Table 3). Neither regression of the residual nodal disease in cases 5, 6, and 7 nor complete tumor responses were observed at the first follow-up CT scan 4 weeks after IORT. Fourteen patients have completed the external irradiation therapy and were available for the second tumor volumetry 18 weeks after IORT. Complete response was achieved in three patients (Fig. 1). In one of them (case 6) the complete response included the lymph nodes as well; in another case (case 5) the residual nodal disease showed a partial regression. In the remaining 11 patients,
IORT in lung cancer, local control 0 F. M. JUETTNERet al.
10 partial responses between 62 and 84% and only 1 minor response of 28% tumor reduction were present (see Table 3). In Patient 5, after an initial 83% PR at 18 weeks, local regrowth of the primary was observed at the margin of the IORT port 30 weeks after IORT. No other case of local relapse was found. At this time, 10 patients are alive and well at a median interval of 12 months after IORT (5 to 20 months). The recent volumetries of their lesions at intervals of 4.5 to 16.5 months after IORT showed 7 CR and 3 PR with 55, 9 1, and 94% tumor regressions. One CR (patient 8), however, was associated with contralateral pulmonary metastasis. DISCUSSION Therapeutic alternatives are needed for patients who either decline thoracotomy with its attendant risks or patients whose underlying pulmonary and other medical problems-most of them related to a history of heavy smoking-make surgery excessively risky ( 16). Tissuesaving wedge-resections or segmentectomies can be done in small subpleural lesions, but they are unsuitable for tumors localized in close contact to large bronchi and vessels. Furthermore, such procedures carry a higher risk of recurrence than lobectomy or pneumonectomy (11). Whereas chemotherapy has shown little benefit in NSCLC (5), conventional radiation therapy is considered an alternative treatment to surgery. Hilton and Smart reported more than 20% of patients surviving more than 5 years after radical radiotherapy for otherwise operable lung cancer (14, 20). However, doses necessary to control T2 or T3 lesions are not applicable by external radiation alone without serious collateral damage. Theoretically, these results might be improved by using IORT, the potential benefit of which results from direct visualization of the tumor. This enables accurate determination of the volume to be treated and the administration of doses that may exceed normal tissue tolerance but which can achieve local control of the tumor while avoiding dosage to the surrounding normal tissue. Today, with fast electrons of various energies available, homogenous dose distributions with rapid fall off beyond the tumor bearing area are possible (1). IORT has been suggested for a variety of neoplasms, first as orthovolt and later as megavolt irradiation. Good results have been reported mainly in pancreatic, biliary, rectal, and prostatic neoplasms, most of which are anatomically unresectable (1, 2, 3, 13, 18). Only a few studies exist concerning lung cancer and IORT. Pass and coworkers completed pneumonectomy or lobectomy, respectively, in four patients, each of whom underwent subsequent 25 Gy IORT of the hilum for residual disease (17). Although no complications were observed in experimental studies in dogs following pneumonectomy and subsequent 20 Gy IORT of the hilum, 2 out of the 4 patients developed life-threatening bronchial
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stump dehiscence and 2 patients died as a consequence of esophageal problems ( 17). Goldson reported four cases treated by IORT of the hilum after the primary had been resected. In one patient who died 6 months after the treatment, esophageal stricture was found. No further information about follow-up is available from this report (13). The largest study on IORT and lung cancer was done by Abe and Takahashi who treated 5 1 patients with NSCLC (2). Detailed data of eight cases are given. The data show an inhomogenous distribution of surgical approach and irradiation schedule: 2 cases were nonresectable, 5 underwent partial resection, and 1 complete resection. Preoperative external irradiation was administered in two patients. The IORT dose ranged between 25 and 30 Gy. The median survival time was 9 months; 5 patients died within the first year (3). We focused our study on primarily functionally unresectable NSCLC which did not infiltrate the mediastinum. The fact that in such cases the tumor-bearing lung remains mobile at the hilum offers the advantage of optimal protection of the vulnerable structures such as heart, spinal cord, esophagus, and large vessels by either surgical manipulation or by shielding techniques (2 1). A postoperative external beam series of treatments of 46 to 56 Gy, respectively, to the mediastinum was scheduled in all patients, including NO cases. We were well aware that at present, postoperative radiotherapy for node-negative disease is controversial ( 10). However, even if no residual disease of NSCLC is suspected by the surgeon or pathologist, about one-half of the patients surviving the operation die within 2 years of locoregional recurrence or metastatic disease (7, 8). Abe and Takahashi noted that due to this metastatic potential lung cancer might be unsuitable for IORT (2). On the other hand, uncontrolled studies suggest some advantages in using postoperative radiation therapy in patients who by resection are found to have involved hilar or mediastinal nodes (9). Therefore, we included external irradiation to optimize the chances of long-term control of the disease. The assessment of remission was based upon CT-scan volumetry. Local tumor control in the chest is difficult to determine, however, because of problems in distinguishing subtle differences between radiation changes and tumor ( 19). Furthermore, bleeding and traumatization at the site of the pulmotomy may also be mistaken for residual neoplasm. We did not state a 100% regression unless any nodular structure left had disappeared and only faint scarring remained at the former site of the tumor, so the actual rate of complete remissions might be higher. The assessment of nodal residual disease after partial lymph node dissection, as present in three cases, was even more difficult. No complete response was observed 4 weeks after IORT, although 14 minor or partial responses with up to 84% regression were found. In three patients no positive effect on residual nodal disease was observed. The fact that lowest percentages of initial tumor regression at that
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May 1990, Volume 18, Number 5
Fig. 1. (a) Case 2: Preoperative findings: T l-lesion in the right lower lobe. subcutaneous emphysema due to 13neumothorax following fine-needle aspiration cytology. (b) Case 2: Findings 4 weeks after IORT: 4% tumor regre! don, localized thickening of the pleura overlying the tumor-bearing area due to surgery. (c) Case 2: Findings after external irradiation: 100% regression, pleural and intrapulmonary scarring.
time wt:re found in the smallest lesions probably reflects the inflluence of surgical artefacts resulting from pulmotomy: tiumor shrinkage might be overlapped by hematoma and edt :ma. In one patient the T2 lesion even increased initially . The degree of remission found at the first checkup
did not allow conclusions to be drawn regftrding the further course of the disease. At the second evaluation, the degree of respo 1Se had improved in all patients. Complete response !WasC bsel-ved in one Tl NO, one T2N0, and one T3N2 lesion In the
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IORT in lung cancer, local control 0 F. M. JUETTNER et al
Fig. 1. (Co&)
latter case, complete response occurred after an external dose of only 26 Gy and also extended to the lymph nodes that had been included in the IORT port. Although the effects of IORT and external irradiation on the tumor can
Table 3. CT-scan
Pt. no. I 2 3 4 5 6 I 8 9 10 11 12 13 14 15
Pretreatment tumor volume (cm3) 40.6 1.1 28.4 16.9 63.6 37.9 41.4 20.5 13.8 28.8 16.4 54.9 18.0 73.5 112.8
cm2 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3
volumetry
and response
Tumor volume 4 weeks after IORT (cm3)/regression (%) 16.8/56 I.414 21.8123 2 1.6/-27* 3 1.7150 12.2168 20.1/50 13.6134 11.8/14 4.7184 13.6117 30.3145 14.0122 17.9176 8 1.6128
hardly be separated in the second CT-evaluation, this particular case shows the curative potential of IORT, as the low external dose will not have contributed essentially to the remission after the short interval of 14 weeks. In
of the primary
tumor
after IORT and after external
irradiation
Tumor volume 18 weeks after IORT (cm’)/regression (%)
Tumor volume at last control (cm3)/ regression (%)
Time of last CT control (ms) since IORT
Survival since IORT (ms) and last degree of remission recorded
15.5162 O.O/lOO 20.5128 5.3169 10.7/83 0.0/100 3.2184 5.6159 0.0/100 5.1169 15.1/72 8.0155 4.1194 71.6163
15.5162 0.0/100 20.5128 0.0/100 0.0183 0.0/100 0.0/100 o.o/ 100 0.0/100 0.0/100 0.0/100 4.819 1 4.1194 Il.6163
4.5 16.5 10.5 13.5 13.5 4.5 10.5 10.5 10.5 10.5 10.5 4.5 4.5 4.5
14 PR (dead) 20 CR (alive) 12 MR (dead) I6 CR (alive) 15 DP(dead) 6 CR (dead) 1 PR (dead) 13 CR (alive)+ 13 CR (alive) 13 CR (alive) 11 CR (alive) 11 CR (alive) 7 PR (alive) 7 PR (alive) 5 PR (alive)
* No initial tumor response is stated in case 4, as due to bleeding artefacts, the CT-scan could not be clearly evaluated. Patient 7 died from intrabronchial hemorrhage 7 weeks after IORT. Disease progression (DP) was observed in case 5 at the margin of the IORT port. + In Patient 8 a contralateral pulmonary metastasis was found after 10 months.
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the second case of nodal residual disease, a marked shrinkage was observed. Satisfactory tumor regressions have been observed in all T stages. There was no correlation with cell type or degree of differentiation. Gross involvement of N2 lymph nodes or a large primary tumor do not necessarily rule out a beneficial effect of IORT and external irradiation, although in N2-disease a long-term curative effect can hardly be expected. One factor influencing the sparse use of IORT in the thorax up to now may have been the uncertainty about side-effects on the thoracic viscera. Recent experimental studies in animals have shown only moderate histological changes of vessels, nerves, and the esophagus at 20-30 Gy, but irreversible fibrotic damage to the lung parenchyma within the irradiation port is unavoidable (6). Large single doses as delivered during IORT carry a risk of cardiac disturbances (6, 12) which in patients with a severely reduced cardiorespiratory function and other underlying diseases must be avoided. Most authors of experimental studies agree, however, that 20 Gy would be a relatively safe dose, if direct irradiation of vulnerable organs can be avoided (18). Very little, however, is known about late toxicity occurring after IORT in combination with additional external irradiation in usual fractionation. We have observed one lethal intrabronchial hemorrhage
May 1990. Volume 18, Number 5
7 weeks after the operation, following an IORT dose of 20 Gy and an external dose of 28 Gy. In retrospect, the tumor showed a marked central necrosis and infiltration of the pulmonary vein in the preoperative CT-scan. In cases such as this, in which hemorrhage is not uncommon even without radiotherapy, IORT might actually be unsuitable. At present, we have been unable to detect any other collateral damage from IORT. This might partly be due to the meticulous shielding of the surrounding organs and partly to the mobility of the lungs at their hilum, which allowed focussing of the beam on the tumor while sparing vulnerable structures. The tumor remissions achieved so far, with a low rate of therapy related complications, are satisfactory preliminary results. However, with only a short follow-up period and a small number of patients, no statements about longterm control of the disease, survival, and late toxicity are possible. The results from previous studies and our personal preliminary observations may suggest that IORT combined with external irradiation could be a therapeutic alternative for a selected group of NSCLC patients who are unsuitable for resection. Further studies will have to be done to evaluate the efficacy of IORT and external irradiation compared to external beam radiation alone, as well as its application in combination with resection and chemotherapy.
REFERENCES 1. Abe, M. Intraoperative radiotherapy-past, present and future. Int. J. Radiat. Oncol. Biol. Phys. 10: 1987- 1990; 1984. 2. Abe, M.; Takahashi, M. Intraoperative radiotherapy: the Japanese experience. Int. J. Radiat. Oncol. Biol. Phys. 71: 863-868; 1981. 3. Abe, M.; Takahishi, M.; Yabumoto, E.; Adachi, H.; Yoshii, M.; Mori, K. Clinical experiences with intraoperative radiotherapy of locally advanced cancers. Cancer 45:40-48; 1980. E.; Nishidai, T.; Takhishi, M. Trials 4. Abe, M.; Yabumoto, of new forms of radiotherapy for locally advanced bronchogenic carcinoma. Strahlen-therapie 153: 149- 158; 1977. 5. Aisner, J.; Hansen, H. H. Commentary: current status of chemotherapy for non-small cell lung cancer. Cancer Treat. Rep. 65:979-986; 198 1. 6. Barnes, M.; Pass, H.; DeLuca, A.; Tochner, Z.; Potter, D.; Tenill, R.; Sindelar, W. F.; Kinsella, T. Response of the mediastinal and thoracic viscera of the dog to intraoperative radiation therapy (IORT). Int. J. Radiat. Oncol. Biol. Phys. 13:371-378; 1987. 7. Carr, D. T. Is staging of cancer of value? Cancer 5 1:25032505; 1983. 8. Carr, D. T.; Mountain, C. T. The staging of lung cancer. Sem. Oncol. 1:229-234; 1974. 9. Choi, N. C. H.; Grillo, H. C.; Gradiello, M. Basis for new strategies in postoperative radiotherapy of bronchogenic carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 6:3 l-35; 1980. 10. Cox, J. D.; Byhardt, R. W.; Komaki, R. The role of radiotherapy in squamous, large cell and adenocarcinoma of the lung. Sem. Oncol. 10:81-94; 1983. 11. Denck, H.; Kutschera, W. Das Bronchuskarzinom aus chirurgischer Sicht. Onkologie 7:263-266; 1984.
12. Gilette, E. L.; McChesney, S. L.; Hoopes, P. J. Isoeffect curves for radiation-induced cardiomyopathy in the dog. Int. J. Radiat. Oncol. Biol. Phys. 11:2091-2097; 1985. 13. Goldson, A. L. Past, present and prospects of intraoperative radiotherapy (IOR). Sem. Oncol. 8:59-64; 198 1. 14. Hilton, G. Present position relating to cancer of the lung: results with radiotherapy alone. Thorax 15: 17- 18; 1960. K.; Ha&l, A.; Juettner, F. M.: 15. Leitner, H.; Arian-Schad, Kohek, P.; Friehs, G. Technical and physical aspects of intraoperative radiation therapy. In: Kaercher, K. H., ed. Progress in radio-oncology, Vol. IV, 1st edition, Vienna: Hofmann; 1988: 237-240. 16. McNeil, B. J.; Weichselbaum, R. R.; Parker, S. G. The fallacy of the five year survival in lung cancer. N. Engl. J. Med. 299:1397-1400; 1978. 17. Pass, H. I.; Sindelar, W. F.; Kinsella, T. J.; DeLuca, A. M.; Barnes, M.; Kurtzmann, S.; Hoekstra, H.; Tochner, Z.; Roth, J.; Glatstein, E. Delivery of intraoperative radiation therapy after pneumonectomy: experimental observations and early clinical results. Ann. Thorac. Surg. 44: 14-20; 1987. radiotherapy. Radiother. Oncol. 18. Rich, T. Y. Intraoperative 6:207-221; 1986. 19. Salazar, 0. M.; Rubin, P.; Brown, J. C. The assessment of tumour response to irradiation of the lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 1: 1107-I 118; 1976. 20. Smart, J. Can cancer of the lung be cured by radiation alone? JAMA 195:1034-1035; 1966. 21. Tepper, J. E.; Gunderson, L. L.; Orlow, E.; Cohen, A. M.; Hedberg, S. E.; Shipley, W. U.; Blitzer, P. H.; Rich, T. Complications of intraoperative radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 10:1831-1839; 1984.
Copyright
0360-3016/90 $3.00 + .oO 8 1990 Pergamon Press plc
??Phase I/II Clinical Trial
INTRAOPERATIVE RADIATION THERAPY COMBINED WITH EXTERNAL IRRADIATION IN NONRESECTABLE NON-SMALL-CELL LUNG CANCER: PRELIMINARY REPORT F. M. JUETTNER, J. SMOLLE,
M.D.,* K. ARIAN-SCHAD, M.D.,+ G. PORSCH, M.D.,+ H. LEITNER, PH.D.,+ M.D.,* F. EBNER, M.D.,’ A.HACKL, M.D.+ AND G. FRIEHS, M.D.* University Medical School of Graz, Austria
Twenty-one patients with nonresectable non-small-cell lung cancer (15 squamous-cell, 4 adeno, 2 large-cell; TlT3, NO-N2, all MO) underwent lymph node dissection and intraoperative irradiation of the tumor (IORT) with doses between 10 and 20 Gy (energies: 7 to 20 MeV electron beam). Postoperatively, 46-56 Gy external beam irradiation (8 or 23 MeV photon beam) were delivered to the mediastinum and 46 Gy to the tumor bearirrg area. Fifteen patients were available for follow-up investigations. The CT-scan tumor volumetry 4 weeks postoperatively showed a significant overall decrease (Wilcoxon test: p < 0.05) with eight minor responses (MR) (tumor regressions between 4 and 45%) and six partial responses (PR) (between 50 and 84%). One case was not evaluable. A second volumetry after external irradiation was done in 14 patients, 18 weeks after IORT, showing 3 complete responses, 10 partial responses (62 to 84%), and 1 minor response (28%). The recent volumetries (10 patients) between 4.5 and 16.5 months after IORT showed 7 complete responses and 3 partial responses (63 to 94%). One patient died from intrabronchial hemorrhage at 7 weeks. Three others died from unrelated causes, 6, 12 and 14 months, respectively, after IORT and in one further case the cause of death at 15 months was local tumor regrowth. Within the median time elapsed since IORT (12 months) only this one case of local regrowth and one further case of distant spread were observed. Lung cancer, Intraoperative radiation therapy, External beam irradiation, Response.
INTRODUCTION
Applied with both palliative and curative intent, the method has shown beneficial effects in a variety of tumors such as pancreatic, biliary, gastric, rectal, prostatic, and cerebral cancers as well as in sarcomas ( 1, 13). In non-small-cell lung cancer (NSCLC), surgery still offers the best chance of cure (5, 1 I), but there is a large number of patients whose tumors are nonresectable for anatomical or functional reasons. In some of these cases IORT might be indicated. Reports exist regarding a total of 59 patients with NSCLC, treated by megavoltage IORT (2, 3, 4, 13, 17’) but only in 13 of them are detailed data about the outcome given (3, 13, 17). Patient selection criteria, surgical treatment, and the radiotherapeutical schedule differed greatly
With intraoperative radiation therapy (IORT) using orthoor megavoltage teletherapy techniques, a single dose of ionizing radiation is delivered directly to the tumor or to the tumor bed at the time of operation (1). As otherwise dose limiting normal tissue can be protected from the beam by physical removal from the treatment field, meticulous focussing, or shielding techniques, the extent of normal tissue irradiation is minimized. This allows the delivery of large doses which can actually achieve control of the tumor. The low degree of collateral damage furthermore enables the use of IORT in combination with resection or external teletherapy (3, 13).
* Dept. Thoracic and Hyperbaric Surgery. + Dept. of Radiotherapy. Part of this paper was presented at the Second International Symposium on Intraoperative Radiation Therapy, Sept. 11- 14, 1988 Innsbruck, Austria, and at the UICC-Workshop on Progress in Regional Cancer Therapy, Nov. 3-5, 1988 Vienna, Austria.
Reprint requests to: F. M. Juettner, M.D., Dept. Thoracic and Hyperbaric Surgery, University Medical School of Graz, A8036 Graz, Austria. Accepted for publication 16 November 1989.
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even within one study, not enabling an objective evaluation of the results. Data about tumor regression are not available from any study. We conducted a controlled Phase I study on IORT and additional postoperative external beam irradiation of the tumor and of the mediastinal drainage area in nonresectable NSCLC. The aim of the study was to determine both the rate and the degree of local tumor response by objective criteria.
METHODS
AND MATERIALS
Since October 1987, we have treated 21 patients with NSCLC (19 males, 2 females; mean age: 65 years, range: 5 l-80; see Table 1). None of these patients could have tolerated radical surgery for lung cancer. During the operation it was discovered that 6 out of the 2 1 patients were nonresectable for anatomical reasons as well. Informed consent was obtained from all patients. Pre-operative evaluation Posterior-anterior and lateral chest roentgenograms, CT-scan, and fibrebronchoscopy were done to determine both type and local extent of the lesion. If no histological diagnosis could be obtained, a fine-needle aspiration cytology was performed. Distant metastases were ruled out by bone-scan and by hepatic sonography. Functional capacity was assessed by cardiopulmonary function tests (spirometry, body-plethysmography, exercise electrocardiogram, ultrasound cardiography, and ventilation-perfusion scan). The detailed causes of nonresectability are listed in Table 1. Surgery Surgery was done inside the radiation therapy room, which is completely equipped as an operating theater. The tumor bearing area was exposed by a posterolateral thoracotomy. In lesions the diagnosis of which had been established cytologically, a specimen for intraoperative frozen section histology was obtained by pulmotomy. The pulmotomy was closed by using absorbable sutures to diminish artefacts from suture material in the follow-up CT-scans. Dissection of Nl and N2-nodes was done in the respective drainage area. In cases 12 and 17 no lymph node dissection was performed, as the nodes had been removed during a preceding intervention. In cases 5, 6, 7, 19,20 infiltration of nodes into the bifurcation did not allow a radical dissection (for localization and pathological tumor stages see Table 1; the stage grouping was done according to the AJC criteria, 1979).
* Satume 25, dual photon therapy, 4, 7, 11, 15, 20, 25 MeV scanning electron beam; manufacturer: Generalelectrics, SGR, France.
May 1990, Volume 18. Number 5
IOR T A linear accelerator* with 4, 7, 11, 15-20, and 25 MeV electron energies was used. The accelerator beam was routinely calibrated every day. This enabled a prospective calculation of dosimetry data for all cone diameters and available energies. The data were listed in tables facilitating a quick determination of the irradiation parameters during irradiation. The choice of the optimal radiation energy and cone diameter in each individual case was based both on preand intraoperative findings. Doses from 10 to 20 Gy at energies from 7 to 20 MeV were delivered at the 90% isodose line (for the individual data see Table 2). Doses less than 20 Gy were only applied, if, due to anatomical reasons, a fully satisfactory protection of the adjacent organs was not possible. Self-manufactured Lucite cones with diameters from 6 to 10 cm were used for the treatment procedure. The cone was firmly put over the tumor and connected to the accelerator by a ring-shaped springsuspended diaphragm, providing a smooth docking. An inner aluminum ring of appropriate size was fitted into the diaphragm to constitute a secondary collimation and reduce lateral electron scatter at the cone wall (15). The direction of the beam was predetermined in a way that provided optimal protection of radiosensitive organs. If anatomically possible, further shielding was achieved with 40 mm thick aluminum sheets or 15 mm thick lead sheets, respectively, inserted between the tumor bearing lung and the underlying tissue. In 12 out of the 2 1 patients, IORT had to be done with both lungs ventilated due to functional reasons. In these cases, absorbable mattress sutures were used to pull the tumor-bearing area into the cone to prevent dislocation. In cases 5, 6, 7, 19, and 20 the incompletely dissected subcarinal lymph nodes were included into the port as far as possible. In Patient 20 infiltrating nodes at the hilum were irradiated separately using a second IORT port. During irradiation, the vital functions were monitored by ECG, continuous arterial blood pressure measurement, and capillary pulse-oxymetry, each of which was displayed outside the radiation therapy room. External irradiation 4 weeks after IORT the patients were scheduled for external beam irradiation on an outpatient basis. The portals were determined by using a simulator and a CTplanning system. Individually manufactured divergent cerrobend blocks were used to deliver a total dose of 46 Gy to the mediastinal lymph nodes and to the primary tumor. In Nl or N2 cases the dose to the mediastinum was increased up to 56 Gy. Either 8 or 23 meVp photon beams were applied, using AP/PA portals with additional
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IORT in lung cancer, local control 0 F. M. JUETTNER et al. Table 1. Pretreatment
No.
Aeetsex
Localization
TNM stage
-
data of nonresectable
Histoloav/aradina
1
68/m
1uL
T2NOMO
Squamous/G3
2
51/m
r1L
T 1NOMO
Squamous/G3
3
68/m
rlL
T2NlMO
Squamous/G2
4
73/f
1IL
T2NOMO
Adeno/GZ
5
74/m
1lL
T2N2MO
Squamous/G3
6
80/m
1uL
T3N2MO
AdenofG2
I
61/m
11L
T3N2MO
Squamous/G3
8
63/m
IUL
TlN2MO
Squamous/G3
9
61/m
IUL
T2NOMO
Squamous/G2
10
66/m
rlL
T2NOMO
Squamous/G3
11
57/m
ruL
TlNOMO
Adeno/GZ
12
65/f
1uL
TINOMO
Large cell/G2
13
73/m
11L
TlNOMO
Adeno/G3
14
70/m
ruL
T3NOMO
Squamous/G2
15
61/m
IUL
T3NOMO
Squamous/G2
16
55/m
rlL
T3N2MO
Adeno/G2
17
63/m
IIL
T 1NOM0
Squamous/G2
18
71/m
ruL
T2NlMO
Adeno/GZ
19
63/m
ruL
T3N2MO
Large cell/G2
20
57/m
1uL
T2N2MO
Squamous/G3
21
55/m
rlL
T3NOMO
Squamous/G3
NSCLC
Cause of unresectability Severe bullous emphysema, transitory ischemic attacks 3 and 5 years ago Cardiac insufficiency. coronary heart disease, severe bullous emphysema Coronary heart disease, bifascicular bloc (pacemaker), hypertension, diabetes melhtus, COLD Coronary heart disease. therapy resistant hypertension, diabetes mellitus COLD, hypertension. cardiac insufficiency N2infiltration into the bifurcation COLD, right ventricular strain, cerebrovascular insufficiency, tumor infiltration into the main pulmonary artery Therapy resistant arrhythmia (Lown 4b), COLD, N2-infiltration into the bifurcation Aortocoronary bypass-obstruction, stenocardia, posterior wall akinesia Cystectomy for bladder cancer T3NOG2; 1982 occlusion of the right iliac artery, bilateral occlusions of crural arteries. COLD Bilateral occlusion of iliac artery, bullous emphysema Myocardial infarction 3 months ago, 60% stenosis of interventricular branch of the left coronary artery (NYHA II; no dilation possible), extrasystoles (Lown IIIb) Myocardial infarction 8 years ago, wedgeresection of lung cancer ( 1uL) 3 years ago COLD, dyspnoea on exertion Cardiac insufficiency, COLD, history of cardiac asthma, dyspnoea on exertion Trifascicular block (pacemaker), coronary heart disease (NYHA II). atheroscleosis Dilatative cardiomyopathy. right ventricular strain, severe obstructive lung disease, diabetes mellitus Severe bullous emphysema, atherosclerosis right ventricular strain Ru-lobectomy 1982, wedge resection of r 1L 1987 both for squamous cell carcinoma, due to COLD no further resection Severe bullous emphysema, hypertensive car diomyopathy. coronary heart disease (NYHA II), dyspnoea on exertion 3 myocardial infarctions in history (no dilation or surgery possible, NYHA III) combined ventilation disorder Combined ventilation disorder, right ventricular strain, schizophrenia Severe obstructive lung disease
r = right; 1 = left: L = lobe.
lateral fields if indicated. 5 times a week.
The fractionation
was 2 Gy/day,
Folio w- up The first post-therapeutic CT-scan was done 4 weeks after IORT, followed by another CT-scan after the external
irradiation series 18 weeks after IORT. Further follow-up included monthly physical examinations and routine chest-roentgenograms as well as CT-scans of the chest and routine blood chemistry every 3 months. Bone-scans, hepatic sonography, and pulmonary function tests were performed at half yearly intervals.
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Table 2. Technical data of irradiation
Pt. no
Tumor diameter (max)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
6 2.5 4 3.5 7 8 6 3 3 3 3 4 3 6 8 5.5 3 4 9.5 3.5
21
7.5 cm
cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm
IORT tumor dose maximum/ radiation energy
Source-surface distance
Cone diameter
20 Gyf20 MeV 10 Gy/ll MeV 15 Gy/20 MeV 15 Gy/15 MeV 17 Gy/15 MeV 20 Gy/15 MeV 20 Gy/l 1 MeV 20 Gy/l5 MeV 20 Gyf20 MeV 20 Gy/ 15 MeV 20 Gy/l 1 MeV 20 Gyf 15 MeV 20 Gy/l 1 MeV 20 Gyj 15 MeV 20 Gy/ 15 MeV 20 Gy/20 MeV 20 Gy/15 MeV 20 Gyf 15 MeV 20 Gy/ 15 MeV 20 Gy/7 MeV 20 Gy/15 MeV 20 Gy/ 15 MeV
100 cm 100 cm 100 cm 91 cm 95 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 100 cm 97 cm 100 cm 100 cm
8 cm 6 cm 8 cm 6cm 10 cm 10 cm 8 cm 6 cm 6 cm 8 cm 6cm 6 cm 6cm 8 cm 10 cm 6 cm 6 cm 6 cm 10 cm 4cm 8 cm (hilar port) 8 cm
External beam irradiation tumor 46 46 46 46 46 26 28 46 46 46 46 46 46 46 46
Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy
Note: In case 6 the external irradiation had to be discontinued for side-effects; in case 7, lethal intrabronchial Doses are calculated at the 90% isodose line. Patients 16-2 1 did not undergo external irradiation.
The assessment of primary tumor regression was based upon volumetry on CT-scans. The radiologist carrying out the measurements was not informed about the therapeutic modalities applied in the respective cases. For the whole group of patients, volumetric pre-treatment and post-treatment values 4 and 18 weeks postoperatively were evaluated by the non-parametric Wilcoxon matched pairs signed rank test. RESULTS
One patient died from unrelated causes 26 days after IORT. Three cases were lost to follow-up and two are still undergoing external beam irradiation. Fifteen patients were available for follow-up investigations. The IORT procedure was well tolerated. Thirteen out of the 15 patients were discharged 1 week after IORT. In case 1 a prolonged bronchopleural fistula due to severe bullous emphysema required intercostal suction drainage for 10 days. In Patient 6, a postoperative hospital stay of 17 days was necessary due to cerebrovascular insufficiency. During the second half of the external irradiation series all patients experienced more or less pronounced sideeffects from radiation treatment which in case 6 caused the treatment to be discontinued after 26 Gy. One patient (7) died from intrabronchial hemorrhage after 28 Gy. Generally, the patients were able to resume their normal life within 1 to 2 months alter the external treatment series.
External beam irradiation mediastinum 46 46 56 56 56 26 28 56 46 46 46 46 46 46 46
Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy Gy
bleeding occurred.
So far, we have been unable to detect any side effects of IORT on the mediastinal viscera, peripheral nerves, or spinal cord. Three patients (1, 3, and 6) died 14, 12, and 6 months, respectively, after IORT due to causes unrelated to the tumor. One patient (5) died at 15 months due to local regrowth of lung cancer. Considering the whole group, tumor volume revealed a significant decrease 4 weeks postoperatively and again 18 weeks postoperatively (Wilcoxon matched pairs test: p < 0.05). The first postoperative evaluation of response by CTscan, 4 weeks after IORT, showed tumor regression in 14 out of the 15 patients: eight cases presented minor responses with a reduction of tumor volume between 4% and 45% (Fig. l), and six patients were found to have partial responses with a tumor shrinkage between 50 and 84%. In case 4 the lesion had increased to 127% of the initial volume (see Table 3). Neither regression of the residual nodal disease in cases 5, 6, and 7 nor complete tumor responses were observed at the first follow-up CT scan 4 weeks after IORT. Fourteen patients have completed the external irradiation therapy and were available for the second tumor volumetry 18 weeks after IORT. Complete response was achieved in three patients (Fig. 1). In one of them (case 6) the complete response included the lymph nodes as well; in another case (case 5) the residual nodal disease showed a partial regression. In the remaining 11 patients,
IORT in lung cancer, local control 0 F. M. JUETTNERet al.
10 partial responses between 62 and 84% and only 1 minor response of 28% tumor reduction were present (see Table 3). In Patient 5, after an initial 83% PR at 18 weeks, local regrowth of the primary was observed at the margin of the IORT port 30 weeks after IORT. No other case of local relapse was found. At this time, 10 patients are alive and well at a median interval of 12 months after IORT (5 to 20 months). The recent volumetries of their lesions at intervals of 4.5 to 16.5 months after IORT showed 7 CR and 3 PR with 55, 9 1, and 94% tumor regressions. One CR (patient 8), however, was associated with contralateral pulmonary metastasis. DISCUSSION Therapeutic alternatives are needed for patients who either decline thoracotomy with its attendant risks or patients whose underlying pulmonary and other medical problems-most of them related to a history of heavy smoking-make surgery excessively risky ( 16). Tissuesaving wedge-resections or segmentectomies can be done in small subpleural lesions, but they are unsuitable for tumors localized in close contact to large bronchi and vessels. Furthermore, such procedures carry a higher risk of recurrence than lobectomy or pneumonectomy (11). Whereas chemotherapy has shown little benefit in NSCLC (5), conventional radiation therapy is considered an alternative treatment to surgery. Hilton and Smart reported more than 20% of patients surviving more than 5 years after radical radiotherapy for otherwise operable lung cancer (14, 20). However, doses necessary to control T2 or T3 lesions are not applicable by external radiation alone without serious collateral damage. Theoretically, these results might be improved by using IORT, the potential benefit of which results from direct visualization of the tumor. This enables accurate determination of the volume to be treated and the administration of doses that may exceed normal tissue tolerance but which can achieve local control of the tumor while avoiding dosage to the surrounding normal tissue. Today, with fast electrons of various energies available, homogenous dose distributions with rapid fall off beyond the tumor bearing area are possible (1). IORT has been suggested for a variety of neoplasms, first as orthovolt and later as megavolt irradiation. Good results have been reported mainly in pancreatic, biliary, rectal, and prostatic neoplasms, most of which are anatomically unresectable (1, 2, 3, 13, 18). Only a few studies exist concerning lung cancer and IORT. Pass and coworkers completed pneumonectomy or lobectomy, respectively, in four patients, each of whom underwent subsequent 25 Gy IORT of the hilum for residual disease (17). Although no complications were observed in experimental studies in dogs following pneumonectomy and subsequent 20 Gy IORT of the hilum, 2 out of the 4 patients developed life-threatening bronchial
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stump dehiscence and 2 patients died as a consequence of esophageal problems ( 17). Goldson reported four cases treated by IORT of the hilum after the primary had been resected. In one patient who died 6 months after the treatment, esophageal stricture was found. No further information about follow-up is available from this report (13). The largest study on IORT and lung cancer was done by Abe and Takahashi who treated 5 1 patients with NSCLC (2). Detailed data of eight cases are given. The data show an inhomogenous distribution of surgical approach and irradiation schedule: 2 cases were nonresectable, 5 underwent partial resection, and 1 complete resection. Preoperative external irradiation was administered in two patients. The IORT dose ranged between 25 and 30 Gy. The median survival time was 9 months; 5 patients died within the first year (3). We focused our study on primarily functionally unresectable NSCLC which did not infiltrate the mediastinum. The fact that in such cases the tumor-bearing lung remains mobile at the hilum offers the advantage of optimal protection of the vulnerable structures such as heart, spinal cord, esophagus, and large vessels by either surgical manipulation or by shielding techniques (2 1). A postoperative external beam series of treatments of 46 to 56 Gy, respectively, to the mediastinum was scheduled in all patients, including NO cases. We were well aware that at present, postoperative radiotherapy for node-negative disease is controversial ( 10). However, even if no residual disease of NSCLC is suspected by the surgeon or pathologist, about one-half of the patients surviving the operation die within 2 years of locoregional recurrence or metastatic disease (7, 8). Abe and Takahashi noted that due to this metastatic potential lung cancer might be unsuitable for IORT (2). On the other hand, uncontrolled studies suggest some advantages in using postoperative radiation therapy in patients who by resection are found to have involved hilar or mediastinal nodes (9). Therefore, we included external irradiation to optimize the chances of long-term control of the disease. The assessment of remission was based upon CT-scan volumetry. Local tumor control in the chest is difficult to determine, however, because of problems in distinguishing subtle differences between radiation changes and tumor ( 19). Furthermore, bleeding and traumatization at the site of the pulmotomy may also be mistaken for residual neoplasm. We did not state a 100% regression unless any nodular structure left had disappeared and only faint scarring remained at the former site of the tumor, so the actual rate of complete remissions might be higher. The assessment of nodal residual disease after partial lymph node dissection, as present in three cases, was even more difficult. No complete response was observed 4 weeks after IORT, although 14 minor or partial responses with up to 84% regression were found. In three patients no positive effect on residual nodal disease was observed. The fact that lowest percentages of initial tumor regression at that
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May 1990, Volume 18, Number 5
Fig. 1. (a) Case 2: Preoperative findings: T l-lesion in the right lower lobe. subcutaneous emphysema due to 13neumothorax following fine-needle aspiration cytology. (b) Case 2: Findings 4 weeks after IORT: 4% tumor regre! don, localized thickening of the pleura overlying the tumor-bearing area due to surgery. (c) Case 2: Findings after external irradiation: 100% regression, pleural and intrapulmonary scarring.
time wt:re found in the smallest lesions probably reflects the inflluence of surgical artefacts resulting from pulmotomy: tiumor shrinkage might be overlapped by hematoma and edt :ma. In one patient the T2 lesion even increased initially . The degree of remission found at the first checkup
did not allow conclusions to be drawn regftrding the further course of the disease. At the second evaluation, the degree of respo 1Se had improved in all patients. Complete response !WasC bsel-ved in one Tl NO, one T2N0, and one T3N2 lesion In the
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IORT in lung cancer, local control 0 F. M. JUETTNER et al
Fig. 1. (Co&)
latter case, complete response occurred after an external dose of only 26 Gy and also extended to the lymph nodes that had been included in the IORT port. Although the effects of IORT and external irradiation on the tumor can
Table 3. CT-scan
Pt. no. I 2 3 4 5 6 I 8 9 10 11 12 13 14 15
Pretreatment tumor volume (cm3) 40.6 1.1 28.4 16.9 63.6 37.9 41.4 20.5 13.8 28.8 16.4 54.9 18.0 73.5 112.8
cm2 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3 cm3
volumetry
and response
Tumor volume 4 weeks after IORT (cm3)/regression (%) 16.8/56 I.414 21.8123 2 1.6/-27* 3 1.7150 12.2168 20.1/50 13.6134 11.8/14 4.7184 13.6117 30.3145 14.0122 17.9176 8 1.6128
hardly be separated in the second CT-evaluation, this particular case shows the curative potential of IORT, as the low external dose will not have contributed essentially to the remission after the short interval of 14 weeks. In
of the primary
tumor
after IORT and after external
irradiation
Tumor volume 18 weeks after IORT (cm’)/regression (%)
Tumor volume at last control (cm3)/ regression (%)
Time of last CT control (ms) since IORT
Survival since IORT (ms) and last degree of remission recorded
15.5162 O.O/lOO 20.5128 5.3169 10.7/83 0.0/100 3.2184 5.6159 0.0/100 5.1169 15.1/72 8.0155 4.1194 71.6163
15.5162 0.0/100 20.5128 0.0/100 0.0183 0.0/100 0.0/100 o.o/ 100 0.0/100 0.0/100 0.0/100 4.819 1 4.1194 Il.6163
4.5 16.5 10.5 13.5 13.5 4.5 10.5 10.5 10.5 10.5 10.5 4.5 4.5 4.5
14 PR (dead) 20 CR (alive) 12 MR (dead) I6 CR (alive) 15 DP(dead) 6 CR (dead) 1 PR (dead) 13 CR (alive)+ 13 CR (alive) 13 CR (alive) 11 CR (alive) 11 CR (alive) 7 PR (alive) 7 PR (alive) 5 PR (alive)
* No initial tumor response is stated in case 4, as due to bleeding artefacts, the CT-scan could not be clearly evaluated. Patient 7 died from intrabronchial hemorrhage 7 weeks after IORT. Disease progression (DP) was observed in case 5 at the margin of the IORT port. + In Patient 8 a contralateral pulmonary metastasis was found after 10 months.
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1. J. Radiation Oncology 0 Biology 0 Physics
the second case of nodal residual disease, a marked shrinkage was observed. Satisfactory tumor regressions have been observed in all T stages. There was no correlation with cell type or degree of differentiation. Gross involvement of N2 lymph nodes or a large primary tumor do not necessarily rule out a beneficial effect of IORT and external irradiation, although in N2-disease a long-term curative effect can hardly be expected. One factor influencing the sparse use of IORT in the thorax up to now may have been the uncertainty about side-effects on the thoracic viscera. Recent experimental studies in animals have shown only moderate histological changes of vessels, nerves, and the esophagus at 20-30 Gy, but irreversible fibrotic damage to the lung parenchyma within the irradiation port is unavoidable (6). Large single doses as delivered during IORT carry a risk of cardiac disturbances (6, 12) which in patients with a severely reduced cardiorespiratory function and other underlying diseases must be avoided. Most authors of experimental studies agree, however, that 20 Gy would be a relatively safe dose, if direct irradiation of vulnerable organs can be avoided (18). Very little, however, is known about late toxicity occurring after IORT in combination with additional external irradiation in usual fractionation. We have observed one lethal intrabronchial hemorrhage
May 1990. Volume 18, Number 5
7 weeks after the operation, following an IORT dose of 20 Gy and an external dose of 28 Gy. In retrospect, the tumor showed a marked central necrosis and infiltration of the pulmonary vein in the preoperative CT-scan. In cases such as this, in which hemorrhage is not uncommon even without radiotherapy, IORT might actually be unsuitable. At present, we have been unable to detect any other collateral damage from IORT. This might partly be due to the meticulous shielding of the surrounding organs and partly to the mobility of the lungs at their hilum, which allowed focussing of the beam on the tumor while sparing vulnerable structures. The tumor remissions achieved so far, with a low rate of therapy related complications, are satisfactory preliminary results. However, with only a short follow-up period and a small number of patients, no statements about longterm control of the disease, survival, and late toxicity are possible. The results from previous studies and our personal preliminary observations may suggest that IORT combined with external irradiation could be a therapeutic alternative for a selected group of NSCLC patients who are unsuitable for resection. Further studies will have to be done to evaluate the efficacy of IORT and external irradiation compared to external beam radiation alone, as well as its application in combination with resection and chemotherapy.
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