The current state of intraoperative interstitial brachytherapy in lung cancer

In:. J. Radialion Oncology EJw/. Pkys.. Vol. Printed in the U.S.A. All rights reserved.

15, pp. I347-

I354 Copyright

0360-3016/8X $3.00 + .OO 0 1988 P~QWIM Press plc

??Original Contribution

THE CURRENT STATE OF INTRAOPERATIVE INTERSTITIAL BRACHYTHERAPY IN LUNG CANCER BASIL S. HILARIS, M.D.,

F.A.C.R. AND NAEL MARTINI, M.D.

Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, NY Low dose-rate intraoperative brachytherapy allows for a more precise tumor localization of the delivered radiation and its easier adaptation to the tumor shape than it is possible with external radiation. As a result a higher dose is usually delivered to the tumor volume and the damage to the normal lung is less. In an attempt to determine the value of lung brachytherapy we provide in this article a complete review of the evolution of brachytherapy in lung cancer at Memorial Sloan-Kettering Cancer Center, an experience which exceeds 1,000 patients. The use of encapsulated sources of I-125, greatly reduced radiation outside the treatment volume and simplified medical and nursing staff radiation protection. Lung brachytherapy in combination with surgery and postoperative external radiation, improved local tumor control in advanced tumors (from 63% to 76%) with no increase in late pulmonary morbidity, but only a modest survival advantage. The results of brachytherapy in patients with early lung cancer who had limited pulmonary reserve, suggest that intraoperative brachytherapy is an effective alternative treatment option. The limited experience with interstitial brachytherapy under fluoroscopic and CT guidance is encouraging, but needs more investigation. Lung cancer, Lung brachytherapy, Lung intraoperative radiation.

had pulmonary interstitial implants with radon-222 with a median survival of 7 months, a 2-year survival of 7% and a 5-year survival of 1.4%.5,” In 1955, Henschke joined Memorial Hospital and introduced two major modifications in the previously used technique; the artificial radionuclides iridium- 192, and for a short period of time gold- 198, as substitutes for radon-222 and the afterloading principle for the insertion of the radioactive seeds.” Since 1956, all interstitial implants have been carried out in our Center by the radiation oncologists. However, interstitial brachytherapy using high energy gamma radionuclides, even with afterloading techniques, proved problematic because of radiation exposure to the operator, patient and everyone in contact with him. The introduction of low energy iodine-125 gamma ray encapsulated sources in 1965 at Memorial Hospital, removed some of these obstables.‘* Subsequent improvements in brachytherapy dosimetry and treatment plan design have made brachytherapy more widely accepted.

INTRODUCTION

The treatment of choice for non-small cell lung cancer is surgical resection. A significant number of patients have non-resectable disease at thoracotomy. The experience at Memorial Hospital over the past 30 years has shown that 15%-20% of all patients brought to thoracotomy have had fairly localized but unresectable tumors amenable to intraoperative interstitial brachytherapy. The first interstitial implant in lung carcinoma was used in conjunction during thoracotomy with pulmonary resection by Graham and Singer’ in 1933. The first implant of a lung carcinoma at Memorial Sloan-Kettering Cancer Center (MSKCC) was performed by Binkley in 194 1 using radon-222 seeds in a patient with an unresectable superior sulcus tumor.3 This patient had excellent palliation for 27 months, but died with brain metastases 35 months later. World War II interrupted this promising beginning and no interstitial implants were performed at Memorial from 1942 until 1948. However, from 1949 through 1955, an average of 20 interstitial implants for unresectable lung tumors were performed each year, all of which were carried out by the thoracic surgeons at the time of the thoracotomy. During the 15-year period from 1941 through 1955, a total of 142 patients

METHODS

AND

MATERIALS

Nearly 7,000 patients with non-small cell lung carcinoma were treated at our Center between 1949 and

Reprint requests to: Basil S. Hilaris, M.D., F.A.C.R., Department of Radiation Medicine, New York Medical College, Valhalla. NY 10595.

Accepted for publication

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29 June 1988.

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1982. During this period over 1,000 patients with nonsmall cell lung carcinoma were found to have either unresectable tumors or significant limitation in their cardiopulmonary reserve as to preclude major resection and were treated by intraoperative interstitial implantation. The types of intraoperative brachytherapy currently used depend on the tumor location and the extent of the gross disease. Discrete lung masses or lymph nodes are treated by permanent implants with iodine- 125 seeds. Chest wall or mediastinal lesions with poorly defined margins or grossly positive margins of resection are treated by either temporary iridium- 192 implants or permanent implants using iodine-125 seeds in absorbable Vicryl suture. Most intraoperative implants are done in patients with a posterolateral thoracotomy, thus providing adequate exposure and access to the area to be treated. An anterior thoracotomy incision is used in selected patients, but this exposure usually does not permit adequate implantation of all gross tumor.

Early experience In 1979 we reported our experience with implantation of unresectable lung carcinoma for the 20-year period ending in 1976.13 During that time, 322 patients with non-small cell carcinoma were treated with permanent interstitial implants. External beam therapy was added routinely when implantation was considered inadequate and in patients who had involved mediastinal lymph nodes (N2). The overall 2-year survival of this group of patients was 15% and the 5-year survival 6%. Survival in patients with negative nodes was 20% (50/ 170) at 2 years and in those with positive nodes 9% (56/152). Local and regional control was obtained in 7 1% of patients with T3NO tumors and 63% of those with Tl-3N2 tumors. However, long-term survival was not achieved despite local control because 38% of the patients with negative mediastinal nodes and 53% of the patients with positive mediastinal nodes developed distant metastases. The most common sites of distant metastases were brain (40%), bone (32%), liver (15%), and contralateral lung (9%). The time interval between thoracotomy and the detection of first metastases is shown in Table 1.

December 1988, Volume 15, Number 6

Table 1. Time of appearance of distant metastases after treatment for the four most common sites in Staae III NSC lung cancer (1956-1976) Time of appearance Failure

Median

Brain Bone Liver Opposite lung

4.5 4.5 7.5 3.5

m m m m

Range 2-24 1-12 2-24 2-12

m m m m

of these patients (7 1%) received, in addition, moderate doses of postoperative external beam radiation to a midplane dose ranging from 3000 cGy in 10 fractions to 4000 cGy in 20 fractions. This combined approach improved the local control from 63% in the earlier series reported to 76%. In the current group the median survival was 26 months and the 2-year survival 5 1%. The most important factor favorably affecting local control and survival, however, was the completeness of resection at thoracotomy (Table 2). Patients with complete resection had a median survival of 36 months and a local control of 86% compared to a median survival of 11 months and a local control of 65% in patients who had incomplete or no resection. Figure 1 shows the radiation response rate in 34 patients with radiologically measurable disease treated by the combination of intraoperative brachytherapy and postoperative external radiation between March 1977 and December 1980. Complete response was defined as disappearance of all signs of measurable disease; partial response was defined as shrinkage of all measurable tumor by at least 50%; and no response was defined as no measurable regression or on the contrary progression of known tumor. Complete response was observed in 24 patients (76%) partial response in seven (2 l%), and no response in one (3%). The overall response rate (complete plus partial) was 97%.13 In 198 1, a randomized study was initiated at MSKCC to determine if adjuvant chemotherapy with vindesine and cisplatin would lengthen the disease-free interval and prolong survival in patients with operatable N2 nonsmall cell lung carcinoma treated by combined surgery, intraoperative brachytherapy, and postoperative exter-

RESULTS

Treatment in N2 disease Between 1977 and 1980, a pilot study was conducted to determine the value of permanent iodine- 125 interstitial implantation of the primary lung tumor, combined with a temporary iridium- 192 implant of the mediastinum, in patients with mediastinal lymph node metastases. I6 The iridium- 192 sources were loaded 3 to 5 days after surgery. A target dose of 3000 cGy to 4000 cGy in 3 to 5 days was delivered during the period under study. Eighty-eight patients with non-small cell lung carcinoma metastatic to mediastinal nodes (N2) were accrued. Most

Table 2. Results in NSC lung cancer with mediastinal adenopathy (T I-3N2) according to intraoperative therapy (1977-1980) Intraoperative therapy Complete resection + brachytherapy Incomplete resection + brachytherapy Brachytherapy only Total

Patients at risk

Local control

Median survival

2-year survival

29

25 (86%)

36 m

70%

36 23 88

27 (75%) 15 (65%) 67 (76%)

13m llm

21% 39% 51%

26m

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Intraoperative brachytherapy in lung cancer 0 B.S.HILARISet al.

PRIMRY

TUHOR RE8PONSE

80T 70 l 50 40

t

30

COMPLETE

PARTIAL NONE

Fig. 1. Response rate in 34 patients with non-small cell lung carcinoma, treated between 1977 through 1980 with intraoperative brachytherapy and postoperative external radiation. (Hilaris, B.S., Gomez, J., Nori, D., Anderson, L.L., Martini, N.: Cancer55 1226-1231, 1985). nal radiation therapy. Patients were stratified according to the extent of resection, (complete resection versus no resection and intraoperative brachytherapy), and according to histology (squamous versus non-squamous cell carcinoma). This study has been closed and the results are currently being analyzed. The preliminary results show no survival advantage in the chemotherapy arm. However, toxicity has been mild, suggesting that this combined approach is well tolerated. Treatment in patients with T3NO disease From 1974 to 1984, 225 patients with Stage T3NO non-small cell lung carcinoma invading the mediastinum (pulmonary artery and/or vein, superior vena cava, pericardium, aorta or esophagus) were treated surgically.4 Forty-nine patients (21.8%) had complete resection, 33 patients (14.7%) had palliative resection combined with interstitial brachytherapy, 10 1 patients (44.9%) had biopsy and intraoperative brachytherapy without resection and 42 patients (18.6%) had only an exploratory thoracotomy and biopsy. The median survival was 17 months, 12 months, 11 months, and 8 months respectively, and the 2-year survival 29%, 30%, 2 l%, and 9% (Table 3). A contemporary group of 44 patients with clinical T3NO mediastinal disease who did not undergo thoracotomy but were treated instead by palliative external radiation and/or chemotherapy was included for comparison. The median survival in this group was 8 months and 2-year survival 10%. It is of interest that incomplete (palliative) resection of the intrathoracic disease combined with intraoperative brachytherapy of the residual gross and postoperative external radiation resulted in a 22% survival at 3 and 5 years. There was no survival advantage in the group of patients treated by complete resection without irradiation.

Table 3. NSC lung cancer with direct mediastinal invasion (T3NO)according to intraoperative therapy (1974- 1984) Intraoperative therapy

Patients at risk

Median survival

2-year survival

Complete resection Incomplete resection + brachytherapy Brachytherapy only Biopsy, no therapy Total

49

17m

29%

33 101 42 225

12m 11 m 8m 12m

30% 21% 9% 22%

Treatment in superior sulcus tumors This presentation, although rare, representing 2-5% of all lung carcinomas,2 deserves special emphasis as it is accompanied by intractable pain, frequently misdiagnosed as cervical arthritis or shoulder bursitis for long periods of 6 to 8 months before a cancer diagnosis is made. l9 Combined preoperative radiation and surgery offer the best survival results in these patients, although favorable results have been reported by resection alone’ or external radiation.6,20 The experience in our institution with 129 consecutive patients who underwent thoracotomy between 1960 and 1982 was recently analyzed and reported.14 Interstitial brachytherapy was used in 103 patients (80%) in whom complete removal of all tumor was not possible. Preoperative external radiation (2000 cGy in five fractions or 4000 cGy in 20 fractions) was used in 82 patients (64%). There was one postoperative death of pulmonary embolism in a patient who had complete resection and no postoperative radiation. Seventeen other patients (13.0%) developed non-fatal complications, including wound infection, empyema, bleeding, atelectasis, and pneumonia. Univariate statistical analysis (excluding the postoperative death), revealed that patients who received preoperative radiation fared better than patients who did not receive it (Fig. 2). The median survival was 23 months with, and 14 months without, preoperative radiation; the 5- and lo-year survivals were 29% and 20%, respectively. Patients who received preoperative radiation, had a 68% local control compared to 57% in those who had no preoperative radiation (Table 4). The differences among those who had complete resection, incomplete resection and brachytherapy, brachytherapy only or no therapy at thoracotomy were not statistically significant. The median survival was 19 months in the 103 patients who had brachytherapy and 16 months in the remaining 25 patients treated without brachytherapy. Percutaneous implantation of chest wall lesions In 1984, a pilot study was initiated to test the feasibility of iodine- 125 percutaneous implantation, in non-small cell lung carcinoma invading the chest wall in patients who refused surgery or were poor risks for thoracotomy.

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December 1988, Volume 15, Number 6

Cl

NO PREOP

(

46

PTS.,

x

PREOP

( 82

PTS.,

TICK

MARK

(I)

INDICATES

LAST

9 CENSORED) 33

CENSORED)

FOLLOW-UP

P = 0.05

00

4’600

96.00

SURVIVAL

1’44. 00

IN

142. 00

2io.

00

2’ae

00

MONTHS

Fig. 2. Actuarial survival in patients with superior sulcus tumors treated with preoperative radiation (82 pts) and without (46 pts).14

with poor pulmonary function or low Karnofsky performance status equal to or less than 50% were eligible. Other eligibility criteria included normal prothrombin time, adequate platelet count (> 1OO,OOO/ mm3) and a normal cardiovascular status. Computerized tomographic (CT) treatment planning was performed to outline the tumor and the target volume to determine the number of iodine-125 sources needed to deliver the prescribed dose ( 16,000 cGy), and to identify the coordinates of each source. A model of the final treatment plan showing the needle entry points, Patients

Table 4. Apical NSC lung cancer (pancoast tumor) results according to intraoperative therapy ( 1960- 1982) Local control Intraoperative therapy Complete resection Incomplete resection + brachytherapy Brachytherapy only Biopsy, no therapy Total

Patients at risk

Preop ERT

No preop ERT

21

82%

50%

60 43 4

66% 68% 0%

68% 52% 25%

128

68% (56/82)

57% (20/46)

angle, depth and loading pattern was constructed to aid in the correct implementation of the planned therapy. The total source strength to be implanted was determined using the iodine- 125 volume nomogram included in the New York System of dosimetry.‘5 To reduce the number of needles, the sources were spaced at 0.5 cm distances along the needle tracks; to reduce further the number of sources, activities in the range of 1.0 to 1.2 mCi were used. The procedure was performed under local anesthesia using biplane fluoroscopic guidance, similar to the one used in percutaneous lung biopsies. A CT scan was taken after the procedure to visualize the sources and determine the final dose distribution. The results in the first seven patients were reported by Heelan et al. in 1987.” Five of the seven patients had this procedure performed at the Outpatient Center and were discharged the same day. No complications were encountered in any of the seven patients. Pain relief was obtained in all four patients who presented with this symptom. Tumor shrinkage was seen in all six patients in whom radiologic followup was available; one patient moved to Florida soon after the procedure and follow-up X rays could not be obtained. Complete response was observed in four patients and partial response in two. The advantages of this technique of thoracic brachytherapy were: (a) eliminating the need for general anes-

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Intraoperative brachytherapy in lung cancer 0 B. S. HILARIS etal.

thesia and a major surgical intervention, (b) avoiding in some patients, the need for hospitalization, and (c) costeffectiveness. Treatment in unresected Stage I or II lung cancer The main reason for unresectability in early stage nonsmall cell lung carcinoma (Stages I and II), is usually severe and irreversible obstructive pulmonary disease, incompatible with further compromise by surgical resection. Only a limited number of reports in the literature refer to the results of radiation therapy with curative intent in early lung cancer.24,28 We have recently reportedI the results of interstitial brachytherapy in 55 patients with Stage I and II nonsmall cell lung carcinoma, who were surgically explored from 1958 through 1984. The age of these patients ranged from 3 1 to 81 years (median 66 years). There were 48 men and 7 women, a ratio of 6.9 to one. Thirtythree patients had squamous cell carcinoma and 22 had adenocarcinoma or large cell carcinoma. The primary tumor was in the right lung in 30 patients, and in the left lung in 25. Partial removal of the primary tumor was possible in 11 patients; the remaining 44 patients had only a biopsy to confirm the diagnosis of cancer. All patients had interstitial brachytherapy using radon-222 (4 patients), iridium-192 (9 patients), and iodine-125 (45 patients). The median tumor dose using iodine- 125 was 16,000 cGy. Postoperative external radiation was given to 24 patients: in 14 patients because of a large primary

STAGE

1 AND OVERALL

2 LUNG CANCER SURVIVAL

T2N0

TIN0

Tl-2N1

LUNG CANCER, BTAGE I & II Fig. 4. Local control rate according to TNM classification in 55 patients with early lung carcinoma treated with intraoperative brachytherapy.”

tumor, in 7 patients because of hilar nodes involvement and in 3 patients because of unsatisfactory implant dose distribution. The postoperative external radiation dose ranged from 2000 cGy in 10 fractions to 5000 cGy in 25 fractions (median 4000 cGy in 20 fractions). There were no postoperative deaths. At the time of the last analysis, 44 patients had died (32 of disease and 12 of unrelated causes); two patients were alive with disease; and nine patients were alive free of disease. The overall 5-year survival calculated by the Kaplan-Meier method, was 32%; and the 5-year local disease-free survival was 63% (Fig. 3). Cox’s multivariate analysis identified two prognostic factors: tumor site and age. The median survival of patients with right lung tumors was 3.44 years compared to 1.33 years in patients with left lung tumors. Patients younger than 58 years had a median survival of 4.5 years versus 2.64 years for patients 58 to 70 years old and 1.57 years for patients older than 70 years. Variables such as sex, histology, stage, type of surgical resection, and radionuclide had no influence on survival. Figure 4 shows the rate of local control according to

Table 5. Stage and histology in 47 long-term survivors Stage I

0

1.0

Years

2,o

from

3,o

4.0

5.0

II III

implant

Fig. 3. Five-year actuarial survival and local disease-free survival in 55 patients with early non-small cell lung carcinoma treated by intraoperative brachytherapy (Hilaris, B.S., Nori, D.).

IV

(AJC) TlNO T2NO T2Nl TlN2 T2N2 T3NO T3Nl T3N2 T3N3 Total

Epid.

Adeno.

LC

GSC

1 : 2 1 17 1 4 27

8

1

4 2

1

18

1

1

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I. J. Radiation Oncology 0 Biology 0 Physics Table 6. Treatment Intraoperative

in 47 long-term survivors

was consistently high in all patients (greater than 80). Table 6 shows the association of long-term survivors with treatment. All patients had thoracotomy; 21 had partial resection leaving gross disease and 26 had only a biopsy to confirm the diagnosis. The main treatment at thoracotomy was an interstitial implant (permanent in 32 patients, temporary in 6, and combined permanent and temporary implant in 9). Additional treatment was given to 28 patients. This consisted of intrapleural instillation of 5 mCi radioactive colloid P32 in 11 patients treated prior to 1970, and external beam radiation to the mediastinum and/or the primary tumor in 20 patients. With the exception of one patient who received 6,000 cGy in 30 fractions, the dose of postoperative external beam irradiation was either 3,000 cGy in 10 fractions (six patients) or 4,000 cGy in 20 fractions (13 patients). All patients were followed until death or if alive to a minimum of 5 years. The median follow-up was 93 months. Twenty-seven of the 47 long-term survivors are still alive and free of their initial lung cancer. Of the remaining patients, 12 died of unrelated causes without evidence of lung cancer, five died oftheir cancer (three with distant metastases) and two are alive with distant metastases. Figure 5 lists the survival in months for each patient. Figure 6 shows the actuarial survival for the two main histological subtypes (epidermoid and adenocarcinoma).

tor and

Postoperative therapy

therapy

P-32 instill (pts)

ERT (pts)

Surg. resect (pts)

Brachy (pts)

Biopsy only (26)

Penn imp1 (24) Perm imp1 + temp imp1 (2) Perm imp1 (8) Temp imp1 (6) Penn + temp imp1 (7)

(9)

(7) (2)

(2)

(47)

(11)

(3) (4) (4) (20)

Incomplete (2 1)

December 1988, Volume 15, Number 6

Total

TNM surgical category: 100% in T 1NO lesions and 70% in the remaining. Patients with hilar disease (Nl) had a higher rate of local control when postoperative external radiation was also given (86% with and 57% without external radiation). Long-term survivors after interstitial brachytherapy The records of 47 patients treated between 1949 and 1982 who were alive at 5 years from their initial diagnosis and treatment were reviewed. All patients were retrospectively staged by using the revised TNM criteria of the American Joint Committee for Cancer (AJC).*’ The age of the 47 long-term survivors ranged from 30 to 76 years (median age 57 years). Of these patients 40 were men and 7 were women. Five patients ( 11%) had Stage I disease, 2 (4%) Stage II disease, 38 (8 1%) Stage III disease, and 2 (4%) Stage IV disease. The TNM categories within each stage were retrospectively identified and listed in Table 5. Note that 11 patients with involved mediastinal lymph nodes (N2) and two patients with supraclavicular nodes (N3) are among the long-term survivors. The histologic cell type was epidermoid carcinoma in 27 patients, adenocarcinoma in 18 patients, large cell carcinoma in 1 patient, and giant and spindle cell carcinoma in 1 patient. The initial performance status based on the Kamofsky scale was an important prognostic fac-

DISCUSSION In spite of the major advances in the diagnosis and treatment of lung cancer the incidence continues to increase. More importantly, only one of every nine patients with lung cancer is expected to survive for 5 or more years.8 The role of radiation therapy in non-small cell lung carcinoma is currently being re-evaluated as to optimal dose and delivery techniques. Several studies have failed to demonstrate convincingly that pre or postoperative

47 LOW&TERtl SURVIVORS AFTER 6RACHVTtlERAPV FOR UNRESECTABLE NON-SllALL CELL LUN6 CANCER (1949-1982)

S U R v

350

;

300

A 1

250

:

150

2oc

100 ; N T Ii S

50 0 1

3

5

7

9

11

13

15

17

PATIENTS

19

21

(0 l-2 ‘22-47

23

25

27

2‘3

31

33

35

37

39

41

43

45

47

I PARTIAL RESECTION; BIOPSY OIILV)

Fig. 5. Survival of 47 patients with non-small cell lung carcinoma treated between 1949 through 1982, who were alive at five or more years after resection (cases l-2 1) or biopsy only (cases 22-47).

lntraoperative

brachytherapy

in lungcancer0

1353

B. S. HILARIS et ai.

CUUU\TIUE PRcwcmLN WJIUING

1 .o

::t.......t.......t.......t.......t.......t.......t.......t.......t.......t.......t.......t.......t..... t t2222222222222222222222222222222222222222222222 1

2 2 2

11 1 11

.BQ t

2

1 1

2 2

11

2

1

2

1 1 111111

2

Adeno

2

1 1 1 1 -60 t

1111111111111

P value = 0.0038

.4Q t

1 111111 1 1 11111

.2Q t

Epidermoid

1 1111 1 1

t

11111 1 1

0.0 t

t

.t.......t.......t.......t.......t.......t.......t.......t.......t.......t.......t.......t.......t..... 30. 90. 150 210 270 330 0.0 60. 120 160 240 300 363

Fig. 6. Actuarial (Kaplan-Meier) survival in non-small cell lung carcinoma according to the two main histologic types, epidermoid and adenocarcinoma.

radiation can prolong survival when combined with surgical resection, despite improvement in local contro1.‘8,26,30,31,33 Radiation sensitizers23*27altered fractionation schedules,22529and combining radiation with chemotherapy 25,32have failed to produce significant benefits. The Radiation Therapy Oncology Group studies suggest that 40-50% of the patients with non-small cell lung carcinoma treated with radiation therapy fail due to local recurrence alone or in combination with distant metastases. Approximately 30% of patients succumb to intrathoracic recurrence alone.’ At present, there is no clear evidence as to the best dose of radiation to control nonsmall cell lung carcinoma. The commonly used fractionation schedules of external irradiation produce a high incidence of interstitial fibrosis that further worsens the pre-existing obstructive lung disease present in many patients with lung cancer.

Pulmonary function testing, including ventilation-perfusion studies, was not performed regularly during the follow-up in our long-term survivors after interstitial brachytherapy. It is therefore, difficult to determine the extent of respiratory insufficiency associated with the intensive but highly localized radiation administered by brachytherapy. We have been, however, impressed by the lack of clinically and radiologically detectable reduction in lung function. We believe that prolonged survival can be achieved by brachytherapy in select patients with unresectable localized non-small cell lung carcinoma. The operative mortality and the postoperative complications are akin to that of exploratory thoracotomy alone. We plan to compare this treatment modality to the use of external irradiation alone in a prospective randomized trial to determine the relative benefits of each in patients with operable non-small cell lung carcinoma found unresectable or incompletely resected at thoracotomy.

REFERENCES 1. Attar, S., Miller, J.E., Satterfield, J., Ho, C.K., Slawson, R.G., Hankins, J., McLaughlin, J.S.: Pancoast’s tumor: irradiation or surgery? Ann. Thorac. Surg. 28: 578-586, 1979.

2. Bertino, F.: Epidemiology of superior pulmonary sulcus syndrome (Pancoast Syndrome). In Advances in Pain Research and Therapy, Vol. 4, John J. Bonica et al. (Eds.). New York, Raven Press. 1982, pp. 15-2 1.

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3. Binkley, J.: Role of surgery and interstitial radon therapy in cancer of superior sulcus of lung. Acta Un. Int. Cancer 6: 1200-1203, 1950. 4. Burt, M.E., Pomerantz, A.H., Bains, M.S., McCormack, P.M., Kaiser, L.R., Hilaris, B.S., Martini, N.: Results of surgical treatment of Stage III lung cancer invading the mediastinum. Surgical Clinics of North America, Vol. 67, No. 5. Philadelphia, W. B. Saunders. October 1987, pp. 987-1000. 5. Clifton, E., Henschke, U., Selby, H.: Treatment of cancer of the lung by interstitial implantation. Cancer 11: 9-l 1, 1958. 6. Devine, J.W., Mendeenhall, W.M., Million, R.R., Carmichael, M.J.: Carcinoma of the superior pulmonary sulcus treated with surgery and or radiation therapy. Cancer 57: 941-943,1986. 7. Emami, B., Perez, C.A.: Carcinoma of the lung. In Principles and Practice ofRadiation Oncology, C.A. Perez, L.W. Bradhy (Eds.). Philadelphia, J.B. Lippincott Co. 1987, pp. 650-683. 8. GAO/PEMD-87- 13: Progress in Extending SutvivaI from I950 to 1982. Washington, D.C., United States General Accounting Office, 1987, p. 67. 9. Graham, E., Singer, J.: Successful removal of entire lung for carcinoma ofbronchus. JAMA 101: 137 l-1374,1933. 10. Heelan, R.T., Hilaris, B.S., Anderson, L.L., Nori, D., Martini, N., Watson, R.C., Caravelli, J.F., Linares, L.A.: Lung tumors: percutaneous implantation of I- 125 sources with CT treatment planning. Radiology 164: 735-740, 1987. 11. Henschke, U.: Interstitial implantation in the treatment of primary bronchogenic carcinoma. Am. J. Roentgenol. 79: 981-987,195s. 12. Hilaris, B.S., Henschke, U.K., Holt, J.G.: Clinical experience with long half-life and low-energy encapsulated radioactive sources in cancer radiation therapy. Radiology 91: 1163-l 167, 1968. 13. Hilaris, B.S., Martini, N.: Interstitial brachytherapy in cancer of the lung: 20-year experience. Int. J. Radiat. Oncol. Biol. Phys. 5: 1951-1956, 1979. 14. Hilaris, B.S., Martini, N., Wong, G.Y., Nori, D.: Treatment of superior sulcus tumor (pancoast tumor). Surgicar Clinics of North America, Vol. 67, No. 5. Philadelphia, W. B. Saunders. October 1987, pp. 965-977. 15. Hilaris, B.S., Nori, D., Anderson, L.L.: New approaches to brachytherapy. In Important Advances in Oncology 1987, V. DeVita, S. Hellman, S. Rosenberg (Eds). Philadelphia, New York, JB Lippincott Co. 1987, pp. 237-26 1. 16. Hilaris, B.S., Nori, D., Beattie, E.J., Martini, N.: Value of perioperative brachytherapy in the management of nonoat cell carcinoma of the lung. Znt. J. Radiat. Oncol. Biol. Phys. 9: 1161-1166,1983. 17. Hilaris, B.S., Nori, D., Martini, N.: Intraoperative radiotherapy in stage I and II lung cancer. Sem. Surg. Oncol. 3: 22-32,1987. 18. Holmes, E.C., Hill, L.D., Gail, M.: A randomized comparison of the effects of adjuvant therapy on resected stage II and III non-small cell carcinoma of the lung. The Lung Cancer Study Group. Ann. Surg. 202: 335-34 1, 1985. 19. Kanner, R.M., Martini, N., Foley, K.M.: Incidence of pain and other clinical manifestations of superior pulmonary

December 1988, Volume 15,Number 6

20.

21. 22.

23.

24.

25.

26. 27.

28. 29.

30.

31.

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