PII S0360-3016(99)00133-9

CLINICAL INVESTIGATION Thoracic

INTRAOPERATIVE 125I BRACHYTHERAPY FOR HIGH-RISK STAGE INON-SMALL CELL LUNG CARCINOMA

ALEX CHEN, M.D.,* MICHAEL GALLOWAY , M.D.,* RODNEY LANDRENEAU, M.D.,†

THOMAS D’A MATO, M.D., PH.D.,† ATHANASIOS COLONIAS, M.D.,* STEPHEN KARLOVITS, M.D.,*ANNETTE QUINN, R.N.,* TIBETHA SANTUCCI, R.N.,† SHALOM KALNICKI , M.D.,* AND

DOUGLAS BROWN, M.D.*

Departments of *Radiation Oncology and†Thoracic Surgery, Allegheny General Hospital, Pittsburgh, PA

Purpose: Preliminary assessment of feasibility, efficacy, acute and chronic side effects associated with permanentintraoperative placement of 125I vicryl mesh brachytherapy in a select group of high-risk Stage I NSCLC whohave undergone video-assisted thoracoscopic resection (VATR).Methods and Materials: From January 8, 1997 to March 16, 1998, 23 patients with Stage I NSCLC at high riskfor conventional surgery due to cardiopulmonary compromise underwent combined VATR and intraoperativeplacement of125I seeds embedded in vicryl mesh. Seeds embedded in vicryl suture were attached with surgicalclips to a sheet of vicryl mesh, and thoracoscopically inserted over the target area (tumor bed and staple line) withnonabsorbable suture or surgical clips. A total dose of 100–120 Gy prescribed to the periphery of the target area(defined as the staple line and tumor bed with a 1-cm margin) was delivered.Results: The mean target area covered was 48 cm2 (range 40–72) and mean total activity was 22 mCi (range17.2–28.2). The median length of postoperative stay was 7 days. The median follow-up was 11 months (range2–20). Postoperative CT scans of the chest revealed no dislodgement of the seeds and no local recurrence in anypatient.Three patients developed distant metastasis (1 died 6 months postoperatively; the other 2 are currentlyalive with disease). One patient developed an ipsilateral recurrence in the right lower lobe after having had aright upper lobe resection. There were 3 postoperative deaths due to medical comorbid conditions or surgicalcomplications (1 in the immediate postoperative period). Pulmonary function testing performed 3 months afterimplantation revealed no significant difference between preoperative and postoperative values: mean preoper-ative FVC was 2.3 L (range 1.31–3.0) and postoperative FVC was 2.2 L (range 1.1–3.9),p 5 0.42; meanpreoperative FEV1 was 1.2 L (range 0.71–2.2 ), and postoperative FEV1 was 1.5 L (range 0.8–2.9),p 5 0.28.Conclusion: Review of early data suggests that intraoperative125I vicryl mesh brachytherapy in high-risk StageI NSCLC is potentially effective and well tolerated, with no significant decline in measurable pulmonary functionstudies and no increase in postoperative complications. Longer follow-up is needed to determine ultimate localcontrol and survival. © 1999 Elsevier Science Inc.

Intra-operative brachytherapy, Video-assisted thoracoscopic resection, Non-small cell lung cancer.

INTRODUCTION

The incidence of lung cancer has been rising over the lastthree decades, with the estimated number of new cases in1998 exceeding 171,500 (1). It has become the leadingcause of cancer death in men, and has surpassed breastcarcinomas as the most frequent cause of death in women(1). In North America, 75% of patients present with early-stage (T1, T2) disease (2); for these patients, lobectomy iscurrently the mainstay of therapy, yielding a 5-year survivalrate of 65–77%. Locoregional recurrence occurs in 28% ofT1N0 tumors submitted to thoracotomy, with the highestinitial failure rates detected in the ipsilateral hemithorax (3,4).

Stage I non-small cell lung cancer (NSCLC) patients with

compromised cardiopulmonary status may undergo limitedsurgical resections in an attempt at lung preservation whileachieving adequate resection margins (5). Video-assistedthoracoscopic resection (VATR) has emerged as a noveltechnique to achieve these objectives. Although VATR of-fers the possibility of resections with decreased postopera-tive recovery time for such patients, local recurrence ratesmay be significant due to the limited resection margin andpotential seeding in the thoracoscopic tract (4, 6, 7). Pre-liminary reports have suggested that adding postoperativelocal “postage-stamp” external beam irradiation to VATRmay improve local control at the expense of increasedmorbidity due to cardiac toxicity, lung fibrosis, and loss ofpulmonary function (8–10).

Intraoperative brachytherapy is an effective therapeutic

Reprint requests to: Alex Chen, M.D., Department of RadiationOncology, 320 East North Avenue, Pittsburgh, PA 15212. Tel:

(412) 359-3400; Fax: (412) 359-3981; E-mail: achen@aherf.eduAccepted for publication 30 March 1999.

Int. J. Radiation Oncology Biol. Phys., Vol. 44, No. 5, pp. 1057–1063, 1999Copyright © 1999 Elsevier Science Inc.Printed in the USA. All rights reserved

0360-3016/99/$–see front matter

1057

modality for patients unable to undergo a formal surgicalresection; it is an alternative to external beam irradiation forpatients who could not tolerate further loss of functioninglung tissue (11, 12). Prior studies have shown improvedlocal control using125I permanent implants as a radiationboost for Stage III NSCLC with paraspinal or chest wallinvolvement (13–16). The authors have developed a novelintraoperative technique utilizing vicryl mesh imbeddedwith 125I-radioactive seeds for thoracoscopic placementover the tumor bed and staple line after VATR. The pilotstudy to determine the technique’s feasibility and morbidityis presented in this publication.

METHODS AND MATERIALS

Patient information and selectionBetween January 8, 1997 and March 16, 1998, 23 patients

with peripherally located Stage I NSCLC underwent com-bined VATR and125I vicryl mesh implantation at AlleghenyGeneral Hospital, Pittsburgh, PA. All patients were stagedaccording to the American Joint Committee for CancerStaging (AJCC) surgical classification. Information ob-tained from computed tomography (CT), bronchoscopy,surgical procedure, and pathology reports were used indefining the stage of disease. Age ranged from 58 to 85years, with a median of 72 years. Histopathologic classifi-cation revealed 12 adenocarcinomas, 6 squamous cell car-cinomas, 4 undifferentiated large cell carcinomas, and 1adenosquamous carcinoma (Table 1).

Preoperative assessment consisted of routine laboratorystudies (complete blood count and chemistries), CT of thechest and upper abdomen, and pulmonary function testing.Operability criteria for VATR included an FEV1 greaterthan 0.6 liters (or less than 70% predicted) and cardiacclearance. Once patients were determined to be VATRcandidates, radiation oncology consultation and informedconsent for implantation were obtained prior to the proce-dure.

Intraoperative implantation was performed if patientswere node-negative on frozen section and had a completelyresected T1 or T2 lesion. Noting that age was not anexclusion criterion is significant, as all patients had pulmo-nary function abnormalities or comorbid conditions thatwould have made a conventional thoracotomy intolerable.

Radioactive source125I was selected as the radioactive source for permanent

implantation; with a half-life of approximately 60 days anda low photon energy of 28 keV, it allows for safe handling,and has a characteristic sharp dose drop-off. The isotopewas furnished in 4.53 0.8-mm cylindrical capsules weldedat both ends; ten seeds spaced 1 cm apart (center to center)were embedded into an absorbable hollow vicryl suturematerial with an attached curved needle on one end (Am-ersham Inc.). The assembly was housed in a stainless steelring that provides complete shielding in a “ready to use”sterile package.

Table 1. Patient and implant characteristics

Patient Age/Sex Stage HistologyTumor size

(cm) No. of seedsActivity/Seeds

(mCi)Total activity

(mCi)Spacing ofseeds (cm)

1 75/F 1A ACA 2.5 40 0.47 19.0 1.02 58/M 1A ACA 3.0 50 0.43 21.5 1.03 74/F 1B ACA 3.5 50 0.40 20.0 1.04 85/F 1B Undiff 10.5 50 0.47 23.5 1.05 65/M 1A SQ 2.0 40 0.60 24.0 1.26 71/M 1A Undiff 2.2 40 0.61 24.4 1.07 66/M 1A ACA 2.5 50 0.41 20.5 1.08 66/M 1A Undiff 1.8 60 0.38 22.8 0.89 79/M 1B SQ 5.0 49 0.35 17.2 1.0

10 77/M 1A ACA 1.5 70 0.32 22.4 0.811 78/M 1A ACA 2.0 50 0.44 24.0 0.812 72/M 1B SQ 7.0 40 0.50 20.0 1.213 78/F 1A SQ 2.0 40 0.51/0.47 19.9 1.214 71/M 1B ACA 2.5 40 0.50 20.0 1.215 76/F 1A ACA 3.0 50 0.41 20.5 0.816 77/F 1A SQ 2.0 70 0.32 22.4 0.717 84/M 1B AdSQ 2.0 60 0.40 24.0 0.818 69/F 1A ACA 1.0 60 0.47 28.2 1.219 65/F 1A ACA 1.5 60 0.39 23.4 1.020 78/M 1A Undiff 1.8 50 0.47 23.5 1.021 78/M 1B SQ 7.0 80 0.34 27.2 0.722 63/M 1B ACA 3.5 40 0.48 19.2 1.523 63/F 1B ACA 1.3 50 0.46 23.0 1.0

* ACA 5 adenocarcinoma; SQ5 squamous cell carcinoma; AdSQ5 adenosquamous; Undiff5 undifferentiated carcinoma.

1058 I. J. Radiation Oncology● Biology ● Physics Volume 44, Number 5, 1999

Implant techniquePatients were submitted to either VATR or mini-thora-

cotomy with a segmentectomy or wedge resection. Thebrachytherapy target area encompassing the tumor bed plusstaple line with a 1-cm margin was determined intraopera-tively. The appropriate spacing between rows was chosenbased upon specific seed activity using a standardizedlook-up table (Table 2). Activity ranged between 0.30–0.60mCi per seed, with spacing between rows adjusted to delivera dose of 100–120 Gy at 0.5 cm. Using a sterile technique,the125I seeds imbedded in vicryl sutures were attached to asheet of appropriately-sized vicryl mesh with sutures and/orsurgical clips at each end (Fig.1). Maximal radiation pro-tection was achieved by use of a custom leaded-plexiglas,autoclavable cage within which the mesh was assembled(Fig. 2). The125I vicryl mesh was then inserted through thethoracoscopy port and sutured over the tumor bed andresection staple line (Fig. 3). As the radioactive mesh wasimplanted with video assistance over a relatively flat resec-tion surface, it would lay over the surgical bed without anysource overlap (Fig. 4). Postoperatively, orthogonal simu-lation films were obtained for placement verification andcomputer dosimetry (Fig. 5). A radiation dose of 120 Gywas prescribed to the periphery of the target volume andcalculated through computerized treatment planning basedon Task Group 43 Report of the American Association ofPhysicists in Medicine (17).

Follow-up assessmentPatients were followed with physical examinations, CT

scans of the thorax, and pulmonary function testing at 3, 6,and 12 months postoperatively. The surveillance intervalwas increased to 6 months if there was no evidence ofdisease after the initial 12 months.

RESULTS

A total of 23 patients were entered into the study. Medianfollow-up was 11 months (range 2–20). All patients under-went segmentectomy or wedge resection with classic 3keyhole incisions. There were 10 patients who required amini-thoracotomy in order to accomplish 16 wedge resec-tions and 7 segmentectomies. The median postoperativelength of stay was 7 days (range 4–36). No acute morbiditywas seen related to the125I vicryl mesh implantation. Therewere 3 postoperative deaths due to comorbid conditions orsurgical complications, with only 1 in the immediate post-operative period. The median implant target area was 48cm2 (range 40–72); average total activity was 22.2 mCi(range 17.2–28.2) delivered through placement of 40–50seeds. Postoperative localization films showed no dislodge-ment or migration of125I seeds. The procedure added ap-proximately 15 min of anesthesia time to VATR. Postoper-ative CT scans failed to reveal a local recurrence within thisrelatively short follow-up period. A small area of pulmonaryfibrosis was seen at the site of implantation in most cases.Three patients developed distant metastasis; 2 are alive aftersystemic chemotherapy, and 1 died 6 months postopera-tively. One patient developed an ipsilateral recurrence in theright lower lobe and chest wall after having had an upperlobe resection with gross tumor spillage during removal; theimplanted resection bed remains locally controlled (Fig. 6).

Table 2. Seed activity look-up table

1.0 cm3 1.0 cm 100 Gy 120 Gy

Size Dose rate @ 0.5 cm Dose rate @ 0.5 cm7 3 7 0.38 mCi/seed 0.46 mCi/seed8 3 8 0.37 mCi/seed 0.44 mCi/seed9 3 9 0.37 mCi/seed 0.44 mCi/seed10 3 10 0.36 mCi/seed 0.43 mCi/seed

1.2 cm3 1.0 cm 100 Gy 120 GySize Dose rate @ 0.5 cm Dose rate @ 0.5 cm

7 3 7 0.42 mCi/seed 0.50 mCi/seed8 3 8 0.41 mCi/seed 0.49 mCi/seed9 3 9 0.41 mCi/seed 0.48 mCi/seed10 3 10 0.41 mCi/seed 0.47 mCi/seed

1.5 cm3 1.0 cm 100 Gy 120 GySize Dose rate @ 0.5 cm Dose rate @ 0.5 cm

7 3 7 0.49 mCi/seed 0.59 mCi/seed8 3 8 0.48 mCi/seed 0.58 mCi/seed9 3 9 0.48 mCi/seed 0.58 mCi/seed10 3 10 0.47 mCi/seed 0.57 mCi/seed

Fig. 1. Attachment of125I radioactive seeds in vicryl suture to asheet of vicryl mesh utilizing sterile technique.

1059Intraoperative brachytherapy for Stage I lung cancer● A. CHEN et al.

Pulmonary function testing performed 3 months afterimplantation revealed no significant difference between pre-operative and postoperative values: mean preoperative FVCwas 2.3 L (range 1.31–3.0) and postoperative FVC was 2.2L (range 1.1–3.9),p 5 0.42; mean preoperative FEV1 was1.2 L (range 0.71–2.2) and postoperative FEV1 was 1.5 L(range 0.8–2.9),p 5 0.28 (Table 3).

DISCUSSION

Conventional lobectomy is currently the standard of careand offers the best survival for Stage I NSCLC patients(40–75%). Approximately 30% of patients with Stage INSCLC are high-risk surgical candidates due to poor gen-eral health, major illness, or marginal cardiopulmonary

Fig. 2. Use of leaded-plexiglas protective shielding for attachment of125I embedded vicryl suture to vicryl mesh.

Fig. 3. Insertion of the125I seeds through the thoracoscopy port with video assistance.

1060 I. J. Radiation Oncology● Biology ● Physics Volume 44, Number 5, 1999

function. They are either observed without any antineoplas-tic therapy or treated with definitive external beam irradia-tion, with overall 5-year survival rates between 13% and21%, which, even with more modern techniques, has notvaried significantly in recent studies (6, 18–27). There arehigh local failure rates (40–70%) and a negative impact onsurvival in several series of radiotherapy alone with tumorsgreater than 3–4 cm when a complete response was not

achieved (25–28). Limitations to these studies include theinadequacy of lymph node staging and selection bias re-garding operability criteria (24).

Fig. 4. 125I-embedded mesh in place over wedge resection staple line/resected tumor bed.

Fig. 5. Postoperative orthogonal simulation film with isodosecurves. Fig. 6. Current patient status.

1061Intraoperative brachytherapy for Stage I lung cancer● A. CHEN et al.

As an alternative, a “compromise” surgical procedure(segmentectomy or wedge resection) was initiated withearly promising results (20); however, more recent analysisin some studies revealed a distinct disadvantage comparedto lobectomy with regard to survival (59% vs. 77%) andlocoregional recurrence (22.7% vs. 50% with wedge resec-tion) (4–7). One of the first studies confirming an increasedlocal recurrence rate was by the Lung Cancer Study Group,which completed a prospective Phase III study to comparelimited resection to lobectomy for peripheral T1N0 lesionsin high surgical risk patients. Results showed a 2.7-foldincrease in locoregional recurrence in the limited resectionarm; patients submitted to wedge resections had the highest(3.5-fold) local recurrence rate (22%, 9/40 patients), ascompared to lobectomy (6%, 9/150 patients), despite nega-tive resection margins (4). Others have reported a trendtoward an increased local recurrence rate with wedge resec-tion and no difference in survival (29).

Advances in video technology allied to the utilization ofsmall intercostal incisions propelled VATR as a novelmethod for the resection of peripheral lung tumors (30–32).Under direct video observation, lung neoplasms can belocalized and resected through thoracoscopically-insertedstapling and laser devices, substituting for the highly inva-sive open thoracotomy. The introduction of VATR hasexpanded the feasibility of surgical removal to higher riskpatients with borderline pulmonary function (5). Main con-cerns regarding widespread use of VATR are the adequacyof surgical margins, the lack of complete surgical stagingthrough formal mediastinal node dissection, and tumorseeding in the operative tract.

Adjuvant limited field or “postage-stamp” external beamirradiation, 50–60 Gy to the operative site, has been deliv-ered in an attempt to decrease local recurrence rates afterconservative lung resections. Results suggest a local recur-rence rate ranging from 6% to 25% (8–9). Little is knownregarding the impact of “postage-stamp” radiotherapy onFEV1 following treatment. In patients with marginal lungreserves, such treatment may have a negative impact onFEV1; however, there is no data available.

Limitations of small-field radiation therapy led to theemergence of intraoperative brachytherapy as a potentialalternative for sterilizing the tumor bed in high risk patients.Early experience from more than 50 years ago utilizing226Ra and192Ir sources yielded marginally positive results,with significant radiation exposure to personnel (33). Thesubsequent development of125I sources, and improvement

in imaging techniques led to more widespread use anddecreased personnel exposure (34, 35). Its use thus far hasbeen limited to inoperable patients or after resections withclose or positive surgical margins, and in cases with chestwall or pleura involvement (13, 33, 35–39). Nori and Hilarishave suggested that intraoperative125I brachytherapy issimple, reproducible, and effective in improving local con-trol in patients with unresectable early-stage and locallyadvanced NSCLC without adding significant morbidity (11,36).

The authors have expanded the procedure as an alterna-tive to external beam irradiation after VATR for early-stagelung carcinoma. Our preliminary results show acceptablelocal control with failures presenting mostly as mediastinaland/or distant recurrences. As expected in this high-riskpopulation, overall survival may be affected by the deliveryof effective systemic therapy. However, in one intraopera-tive mesh placement, one could potentially elicit the samelocal control benefit as in 6–7 weeks of external beamirradiation with significantly decreased pulmonary morbid-ity. An important preliminary conclusion of this study is theabsence of detrimental effects on pulmonary function fol-lowing intraoperative implantation, with an actual slightimprovement of mean FEV1 being observed postopera-tively. This observation is consistent with other studies thathave assessed pulmonary function after conservative lungresections without postoperative irradiation (3, 40).

The non-cancer related death in three of our patients(13%) is actually less than would be predicted for an olderhigh-risk group, comparing similar data in a study byNoordijk, who found the survival of patients more than 75years of age, treated by local radiotherapy, was equal to thesurvival of those treated with surgery alone (19). It is areflection of the age and high medical risk of this patientpopulation. As follow-up time increases, the cancer-specificsurvival and local control data will be tracked.

CONCLUSION

The association of VATR with intra-operative125I vicrylmesh brachytherapy is a well-tolerated and potentially ef-fective therapeutic approach for early-stage NSCLC pa-tients who are not candidates for conventional surgicalintervention secondary to cardiopulmonary compromise.Preliminary observations show that local control is at leastcomparable to external beam irradiation, while there is nosignificant decrease in pulmonary function.

The role of intraoperative brachytherapy for NSCLC willlikely gain momentum as the use of thoracoscopic surgerybecomes more widespread.125I vicryl mesh placement canbe easily reproduced. Further follow-up is obviously re-quired. Future research directed at decreasing the regionaland/or distant failure rate through the addition of mediasti-nal irradiation and systemic chemotherapy is being carriedout in an attempt at improving survival and quality of lifefor this highly challenging group of patients.

Table 3. Preoperative and postoperative pulmonaryfunction testing

Preoperative FVC✣ 5 2.3 liters (range 1.3–3.0)FEV1l 5 1.2 liters (range 0.7–2.2)

Postoperative FVC✣ 5 2.2 liters (range 1.1–3.9)FEV1l 5 1.5 liters (range 0.8–2.9)

✣ p-value5 0.42,lp-value5 0.28

1062 I. J. Radiation Oncology● Biology ● Physics Volume 44, Number 5, 1999

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