2004;78:1224-1228 Ann Thorac SurgReichwage, Karen M. Rieger, Lawrence H. Einhorn and John W. Brown

Rafael S. Andrade, Kenneth A. Kesler, Jamison L. Wilson, Jo Ann Brooks, Brett D. Tumors After Bleomycin-Combination Chemotherapy

Short- and Long-Term Outcomes after Large Pulmonary Resection for Germ Cell

http://ats.ctsnetjournals.org/cgi/content/full/78/4/1224located on the World Wide Web at:

The online version of this article, along with updated information and services, is

Print ISSN: 0003-4975; eISSN: 1552-6259. Southern Thoracic Surgical Association. Copyright © 2004 by The Society of Thoracic Surgeons.

is the official journal of The Society of Thoracic Surgeons and theThe Annals of Thoracic Surgery

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hort- and Long-Term Outcomes After Largeulmonary Resection for Germ Cell Tumors Afterleomycin-Combination Chemotherapy

afael S. Andrade, MD, Kenneth A. Kesler, MD, Jamison L. Wilson, MS,o Ann Brooks, DNS, Brett D. Reichwage, MS, Karen M. Rieger, MD,awrence H. Einhorn, MD, and John W. Brown, MDepartment of Surgery, Thoracic Division, and Department of Medicine, Oncology Division, Indiana University School of

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Background. Treatment of nonseminomatous germ cellumors frequently requires bleomycin-combination che-

otherapy followed by resection of residual disease.leomycin administration however raises concerns with

espect to postoperative respiratory complications, par-icularly for patients undergoing large pulmonary resec-ions. We undertook an institutional review to determinehe outcome of large pulmonary resections after bleomy-in-combination chemotherapy.

Methods. Between 1981 and 2001, 530 patients pre-ented to our institution for resection of residual in-rathoracic disease for either metastatic testicular or pri-

ary mediastinal nonseminomatous germ cell tumors.e subsequently reviewed 32 of these patients who

equired pneumonectomy (n � 19; right � 9, left � 10) orilobectomy (n � 13) after bleomycin-combination

hemotherapy.

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2004 by The Society of Thoracic Surgeonsublished by Elsevier Inc

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Results. There were four operative deaths (13%). Allostoperative deaths occurred in patients undergoingight-sided resections (pneumonectomy, n � 2; bilobec-omy, n � 2) as a consequence of pulmonary complica-ions. Operative survivors had a pulmonary morbidity of8%. Fourteen of 20 long-term survivors were found toave a satisfactory performance status at follow-up.Conclusions. Otherwise young and healthy male non-

eminomatous germ cell tumors patients requiring largeulmonary resections after bleomycin-combination che-otherapy appear to be at higher than anticipated risk

or pulmonary-related morbidity and mortality. Howeverong-term survivors report an acceptable functional sta-us.

(Ann Thorac Surg 2004;78:1224–9)

© 2004 by The Society of Thoracic Surgeons

onseminomatous germ cell cancers (NSGCT) serveas premiere models for multimodality cancer ther-

py with cisplatin-based combination chemotherapy fol-owed by surgical resection of residual disease. This

ultimodality therapy results in long-term cure rates of0% to 90% for NSGCT of testicular origin and 50% to0% for NSGCT primarily originating in the mediasti-um [1, 2]. Bleomycin in combination with cisplatin andtoposide is believed to represent the optimal chemo-herapeutic regimen for NSGCT and in particular forreatment of high-risk NSGCT cases [3, 4]. However,ulmonary toxicity, including interstitial fibrosis, is anown potential consequence of bleomycin therapy4–6]. The potential for pulmonary toxicity raises con-erns regarding postoperative pulmonary morbidity. Weave previously reported low operative risks for NSGCTatients, including patients who require lobar resection

1, 2, 7]. We have, however, observed that the majority ofatients experiencing operative morbidity and mortalityequired large pulmonary resections (pneumonectomy

ccepted for publication March 30, 2004.

ddress reprint requests to Dr Kesler, Indiana University School ofedicine, Department of Surgery, Thoracic Division, 545 Barnhill Dr, EH

PN] or bilobectomy [BL]) to remove residual disease.he purpose of this study was to review our institutionalxperience regarding the short-term and long-term out-omes of large pulmonary resection after bleomycin-ombination chemotherapy for metastatic testicularSGCT or primary mediastinal NSGCT.

aterial and Methods

atient Identificatione initially reviewed our institutional records of 530

atients who underwent resection of residual intratho-acic disease after platinum-based combination chemo-herapy for either metastatic testicular NSGCT (n � 422)r primary mediastinal NSGCT (n � 108) between 1981nd 2001. We identified a subset of 32 patients whoequired large pulmonary resections (metastatic testicu-ar NSGCT, n � 22; primary mediastinal NSGCT, n � 10)efined as either PN or BL after bleomycin-combinationhemotherapy regimens, and these patients are the basisf this report. Formal Institutional Review Board ap-roval was obtained before hospital record review andatient contact. Our standard thoracic surgical care for

SGCT patients has been described elsewhere [1, 2].

0003-4975/04/$30.00doi:10.1016/j.athoracsur.2004.03.081

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1225Ann Thorac Surg ANDRADE ET AL2004;78:1224–9 LARGE PULMONARY RESECTION AFTER BLEOMYCIN

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owever, to summarize, all patients received standardhoracic surgical care with aggressive perioperative pain

anagement including epidural catheter analgesia andudicious intravenous fluid administration. Additionally,nspired oxygen concentrations were maintained at min-mum levels to achieve arterial oxygen saturations of 90%r greater [3, 6, 8]. Patients were allowed at least 4 to 6eeks of recovery after chemotherapy before surgery.ince 1992, all PN patients at our institution, includingSGCT cases, have undergone reinforcement of theronchial stump with a rotated flap of adjacentericardium.

ariables and Analysissing a structured data collection form, multiple vari-

bles were collected, including patient demographics;rigin of NSGCT; chemotherapy variables including tim-

ng with respect to surgical therapy and total dose ofleomycin; surgical variables including the specific sur-ical approach (sternotomy, thoracotomy, or clamshellilateral thoracotomies), type of large pulmonary resec-

ion (right or left PN, right upper and middle or middlend lower BL), and resection of other adjacent intratho-acic structures such as pericardium, phrenic nerve, greateins, and diaphragm; and pathologic category of theesidual mass (necrosis, teratoma, persistent NSGCT,nd non–germ cell cancer). All complications occurringuring the hospitalization were recorded and categorizeds pulmonary and nonpulmonary. Operative mortalityas defined as death occurring within 30 days of surgeryr during the hospitalization if greater than 30 days.unctional status was assessed by a nine-question sur-ey, including functional ability according to the Easternooperative Oncology Group (ECOG) scale and require-ent for supplemental oxygen. Information on operative

urvivors was categorized as alive without evidence ofisease, alive with evidence of disease, tumor-relatedeath, non–tumor-related death, and lost to follow-up.asic descriptive statistics for parametric and nonpara-etric data were used to characterize the sample when

eemed appropriate. Kaplan-Meier analysis was used toalculate overall and pathologic-specific survival for op-rative survivors.

esults

he sample was composed of all males, and the majorityere young white men with a mean age at diagnosis of 278 years. The median total dose of bleomycin was 360 IU

n � 31, range 120 to 360 IU). Bleomycin dosage was notvailable for 1 patient. Eighteen (60%) of the 31 patientsith available chemotherapy data received a standard

otal dosage of 360 IU. Only 1 patient received a briefourse of steroids for clinical evidence of bleomycinoxicity during chemotherapy. Six patients (19%) addi-ionally received second-line platinum-based chemo-herapy without bleomycin before surgery. Large pulmo-ary resections were performed after a median intervalf 3.1 months (range, 0.7 to 91 months) after bleomycin-

ombination chemotherapy. Twenty of 32 patients (63%) c

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nderwent one thoracic surgical procedure for resectionf residual disease, 9 (28%) had two procedures, and theemaining 3 patients had three or more total thoracicurgical procedures. Five of these additional thoracicurgical procedures after large resection included pulmo-ary wedge resection. The surgical approaches used for

arge pulmonary resection included thoracotomy in 2578%), clamshell in 5 (16%), and sternotomy in 2 (6%).ineteen patients (59%) underwent a PN (right PN, n �

; left PN, n � 10), and 13 (41%) underwent a BL. Nine ofhe BLs were middle and lower lobectomies with theemaining four involving the upper and middle lobes.ighteen (56%) patients underwent resection of adjacentericardium, 9 (29%) patients had resection of the ipsi-

ateral phrenic nerve, 7 (32%) patients had partial resec-ion of the ipsilateral diaphragm, and 4 patients (13%)ad resection of a great vein. Eight (25%) of the largeulmonary resections pathologically demonstrated tu-or necrosis only, 7 (22%) demonstrated benign tera-

oma, and 10 (31%) and 7 (22%) had elements of persis-ent NSGCT and degeneration into non– germ cellancer, respectively.

The overall operative mortality was 13% (n � 4), andccurred only in patients undergoing right-sided resec-ions (PN, n � 2; BL, n � 2, both upper and middleobectomies); thus the operative mortality for large right-ided lung resections was 18% (4 of 22). Three of theseour patients had also required phrenic nerve resectionor tumor involvement. Two of 5 patients undergoingight-sided large pulmonary resection, which includedn bloc ipsilateral phrenic resection, survived. All fourperative deaths were attributable to acute respiratoryistress syndrome (ARDS). One patient demonstratedrogressive respiratory failure secondary to uncompli-ated ARDS with the other three cases of ARDS compli-ated by secondary pneumonia (n � 1) and microscopicvidence of diffuse pulmonary arteriolar thrombi (n � 2)n postmortem examination. Patient and surgical vari-bles in operative mortality cases are shown in Table 1.he 4 patients who died postoperatively spent an averagef 14 � 4.7 days (range, 10 to 21 days) on mechanicalentilation and were hospitalized for a mean of 17.5 � 5.4ays (range, 10 to 22 days).Six of 28 operative survivors (21%) had one or more

onfatal complications, which are summarized in Table. Pulmonary complications were most common andccurred in 5 (18%) patients, including one nonfatal casef each of ARDS (n � 1) and pneumonia (n � 1). Bothatients required prolonged mechanical ventilation (8nd 4 days, respectively). One additional surviving pa-ient required reintubation for bronchoscopy and controlf retained secretions. A nonfatal, nonpulmonary com-lication or complications occurred in 5 (18%) patients,

ncluding atrial fibrillation (n � 1), transient renal dys-unction (n � 3), and nonpulmonary sepsis (n � 3). Thereere no complications secondary to poor airway healing,

ncluding bronchopleural fistula. The overall averageength of hospital stay in the 22 operative survivors whoid not experience complications was 8.0 �2.4 days as

ompared with an average of 17.4 �7.9 days for patients

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xperiencing one or more complications. Four of the 5urviving patients who demonstrated pathologically per-istent NSGCT in the surgical specimen and a clinicalesponse to preoperative chemotherapy received twodditional courses of cisplatin and etoposide adjuvanthemotherapy after recovery [2, 9].

The mean duration of follow-up was 27 months (range,to 148 months) for the 28 patients who survived the

urgical procedure. At the time of last follow-up, 14 (50%)ere alive without disease, 5 (18%) were alive withisease, and 8 (29%) had died of disease. Only 1 patientas lost to long-term follow-up. The Kaplan-Meier sur-

ival curves for operative survivors (n � 28) and byathologic category are shown in Figure 1. Long-termurvival was dependent on pathologic category of theurgical specimen and not unexpectedly was better inatients with postchemotherapy pathologically demon-trated benign residual disease (p � 0.0026). Of the 13atients with pathologically demonstrated benign dis-ase, all were alive at the time of follow-up (range, 1 to48 months).Fourteen of the 20 long-term survivors were available

or evaluation of their functional status, and all reportedn Eastern Cooperative Oncology Group functional sta-us of either 0 (fully active and able to perform allctivities without restriction, n � 5) or 1 (restricted inhysically strenuous activity but ambulatory and able toarry out work of a light or sedentary nature, n � 9). Oneatient required supplemental oxygenation at the time ofvaluation 15.8 months after surgery. This patient ratedimself as an Eastern Cooperative Oncology Group sta-

able 1. Description of Operative Deaths (n � 4)

geType of Right-Sided

Lung ResectionBleomycinDose (IU)

7 PN 3602 PN 3009 BL 3609 BL 300

RDS � acute respiratory distress syndrome; BL � bilobectomy;

able 2. Nonfatal Operative Morbiditya

orbidity n (%)

ulmonary (n � 5)Pneumonia 1 (4)ARDS 1 (4)Atelectasis requiring bronchoscopy 2 (7)Prolonged air leak (�10 days) 2 (7)Discharged with supplemental oxygen 1 (4)onpulmonary (n � 5)Atrial arrhythmia 1 (4)Nonpulmonary sepsis 3 (11)Transient renal dysfunction 3 (11)

Patients may have experienced one or more complications (n � 28).

RDS � acute respiratory distress syndrome. a

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us 1 at this time. No other long-term pulmonary-relatedorbidity or mortality has been reported.

omment

leomycin, an antibiotic produced by the fungus Strepto-yces verticillus, has been found to be useful in the

reatment of a variety of neoplasms, including lympho-as and oropharyngeal malignancies, as well as germ

ell tumors. The combination of cisplatin, etoposide, andleomycin chemotherapy with subsequent surgery foresidual disease has been demonstrated to be highlyurative for germ cell cancers that were previously fatalhortly after diagnosis. Bleomycin causes cell death byacilitating the production of oxygen radicals, resulting inNA chain disruption [10–12]. A hydrolase enzyme in-

ctivates bleomycin, which is present in all tissues excepthe lungs and skin [13]. Pulmonary toxicity, therefore, ishe predominant adverse consequence from a clinicaltandpoint. In animal models, bleomycin-induced pul-onary toxicity begins with endothelial cell damage,hich is followed by an acute inflammatory response,

ncluding invasion of white blood cells into the intersti-ium [14]. Lymphocytes bound to endothelial cells acti-

Surgical Pathology Cause of Death

Persistent NSGCT ARDSTumor necrosis ARDS/Arterial ThrombiPersistent NSGCT ARDS/Arterial ThrombiPersistent NSGCT ARDS/Pneumonia

T � nonseminomatous germ cell cancer; PN � pneumonectomy.

ig 1. Long-term overall survival for patients who underwent largeulmonary resection. Curves depict long-term survival of the over-ll series (n � 28) and by postchemotherapy disease, benign (n �3) versus malignant (n � 15). Numbers represent patients at risk

NSGC

t the 20-, 40-, and 60-month intervals for each group.

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ate fibroblasts to deposit collagen, which completes therocess [8, 15–17].The reported incidence of bleomycin-induced pulmo-

ary toxicity ranges from 3% to 40% and appears to beose related. The likelihood of clinically evident bleomy-in-induced pulmonary toxicity appears to be lower if theotal bleomycin dose is less than 300 to 400 IU [4–6, 8].leomycin-induced pulmonary toxicity is considered toe partially reversible with steroid therapy; however, theegree of reversibility is difficult to assess, and progres-ion has been described even after completion of chemo-herapy [8, 18–21]. Although only 1 patient in this seriesndergoing large pulmonary resection had clinical evi-ence of pulmonary toxicity during bleomycin combina-

ion chemotherapy, some degree of residual nonclinicallyvident toxicity is of concern, as this may predispose aatient to postoperative ARDS. Donat and Levy [5] re-orted a 25% incidence of major postoperative respira-

ory problems after mostly retroperitoneal lymph nodeissection for residual NSGCT disease after bleomycinombination chemotherapy in 77 patients. Such an inci-ence of major respiratory problems is clearly higher

han would otherwise be expected in a young population.f bleomycin combination chemotherapy predisposes toostoperative ARDS after abdominal surgery, then legit-

mate concerns would clearly be raised in patients withimilar age and sex demographics undergoing largeulmonary resections, in particular because ARDS and

he so-called post-PN syndrome are already well-knownnd dreaded complications.The vast majority of patients presenting with primaryediastinal NSGCT and approximately 10% to 20% of

atients presenting with metastatic testicular NSGCTltimately require a thoracic surgical procedure to re-ove residual disease after chemotherapy [2]. We have

reviously reported operative mortalities of 4% and 1%,espectively, in primary mediastinal NSGCT and meta-tatic testicular NSGCT patients undergoing resection ofesidual intrathoracic disease, with the majority of oper-tive mortality after large anatomic pulmonary resection1, 2, 7]. In this report, we studied a subpopulation ofSGCT patients with residual intrathoracic disease afterleomycin combination chemotherapy that required BLr PN. All operative deaths in our study were secondaryo pulmonary complications, and occurred in patientsndergoing right-sided resections, with an overall mor-

ality of 13% and 18% mortality specific for right-sidedesections. Pneumonectomy for non–small cell lung can-er without neoadjuvant chemotherapy can be per-ormed with an overall reported mortality of 3% to 7%.ight PN, however, has been identified as having aignificantly higher mortality primarily because of anncreased frequency of the so-called post-PN syndromes well as increased incidence of bronchial stump leakages compared with left PN [22, 23]. Neoadjuvant non–mall cell lung cancer therapy appears to be an additionalisk factor for right PN. In a large retrospective studyrom Memorial Sloan Kettering, the 30-day mortality foright PN after neoadjuvant chemotherapy was 24%, with

espiratory causes predominating [24]. The demograph- h

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cs as well as comorbid risk factors of patients withSGCT obviously differ significantly from lung canceratients. Lung cancer patients are generally in their sixth

o seventh decade of life, and approximately half havereexisting comorbidities such as chronic obstructiveulmonary disease, which equates to relatively pooreserve after any type of pulmonary resection. Althoughisk data for large pulmonary resections in a cohort oftherwise young and healthy men are lacking, we wouldstimate the risks observed in our series to be three-foldo five-fold higher than expected.

As postoperative ARDS is the predominate cause of andverse outcome, we use several common strategies tovoid this complication, which are not necessarily uniqueo NSGCT patients. These strategies include aggressiveain management with epidural catheter analgesia, min-

mizing perioperative fluids administration, and a con-ervative extubation policy with extubation usually de-erred until the first postoperative day to avoid earlytelectasis in the remaining lung parenchyma. We havelso adapted several strategies, which are perhapsnique to NSGCT patients. Although small patient num-ers prohibit meaningful statistical analysis, it appears

hat the combination of a large, right-sided pulmonaryesection with en bloc removal of the ipsilateral phrenicerve carries a higher risk. Loss of diaphragmatic func-

ion may impair breathing mechanics of the remainingontralateral lung. Many residual masses after chemo-herapy for NSGCT contain no malignant elements or, if

alignant elements are present, they may be more cen-rally located within the residual mass. We thereforevoid phrenic nerve resection if the residual disease isbutting but not involving the phrenic nerve with frozen-ection control of the surgical margin [1, 2, 9]. Diaphrag-atic plication after PN may be a consideration in an

ttempt to improve contralateral respiratory mechanics;owever, plication after BL could potentially lead toleural space complications [25].Minimizing inspired oxygen concentrations during

nd after surgery is believed to have a beneficial effect onmeliorating the potential toxic effects of bleomycin [3, 6,]. In this regard we have more recently aggressivelylaced prophylactic temporary tracheostomy tubes at the

ime of surgery in high-risk NSGCT cases to not onlyacilitate ventilator weaning but also optimize secretionontrol. Finally, a finding of concern is the diffuse micro-hrombi in pulmonary arterioles in remaining lung pa-enchyma found on postmortem examination in 2 pa-ients in this series. We can only speculate as to theauses of this finding, including low pulmonary bloodow as perhaps a preterminal event or related to preex-

sting endothelial cell damage from bleomycin. Based onhese postmortem observations, however, we have also

ore recently used judicious anticoagulation in NSGCTatients with early clinical signs of impending ARDS.In summary, we found an increased risk of pulmonary-

elated morbidity and mortality after large pulmonaryesections in NSGCT patients after bleomycin combina-ion chemotherapy regimens. Despite these relatively

igh risks, surgical therapy is warranted for any NSGCT

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atient with anatomically resectable residual diseasefter chemotherapy, as many NSGCT patients willchieve long-term disease-free survival even with patho-ogic evidence of residual malignant elements. Addition-lly, long-term survivors appear to have acceptable func-ional reserve. Our current research efforts are focusedn identification of histochemical evidence of bleomycin-

nduced lung injury and correlation of these data withespect to dose and timing of surgery after bleomycinombination chemotherapy. Until further data arenown, as bleomycin is arguably the least importantomponent of the three-drug combination treatment reg-men from an oncologic standpoint and pulmonary tox-city does appear to be dose related, we currently recom-

end limiting bleomycin to 300 total units if a largeulmonary resection is anticipated.

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8. Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001;120:617–24.

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araccPpbtpNt

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NVITED COMMENTARY

lthough this article deals with a rare indication forulmonary surgery, the report has much broader impli-ations. The lessons from the study are relevant tohoracic procedures for other diseases; pulmonary resec-ions after preoperative treatment, and the proper hand-ing of the diaphragm on the side of a pneumonectomy ifhe phrenic nerve has been resected.

The authors present an impressive experience withajor lung resections for germ cell tumors that have

een treated with chemotherapy. Indiana University haseen a leader in developing optimal management ofuids and oxygen when operating for germ cell tumors

fter the patient has been treated with bleomycin. Cur-ently, thoracic operations after preoperative chemother-py are now commonplace for lung cancer, esophagealancer, malignant pleural effusions, stage III thymic can-er, and pulmonary mets from multiple malignancies.ulmonary toxicity, including interstitial pneumonitis,ostoperative ARDS, and pulmonary fibrosis, has noween reported after treatment with more than 20 chemo-herapy drugs. Neoadjuvant treatment with carbo-latinum and Taxol (Bristol-Myers Squibb, New York,Y) increase the mortality for right pneumonectomy

hreefold. When operating upon any patient who has

0003-4975/04/$30.00doi:10.1016/j.athoracsur.2004.06.079

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2004;78:1224-1228 Ann Thorac SurgReichwage, Karen M. Rieger, Lawrence H. Einhorn and John W. Brown

Rafael S. Andrade, Kenneth A. Kesler, Jamison L. Wilson, Jo Ann Brooks, Brett D. Tumors After Bleomycin-Combination Chemotherapy

Short- and Long-Term Outcomes after Large Pulmonary Resection for Germ Cell

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