P-616 Ramifications of severe organ dysfunction in newly diagnosed patients with small cell lung cancer

$280

Posters / Non-small ceil lung c a n c e r - Early disease (I-IliA)

importance of sul>collular Iocalr~ation (nuclear versus cytoplasmic) of o/din D1 naeds avaluafion We carried out a rretrespac0ve study of pafients with stage I NSCLC with tha obje~ve to evaluate the association of nuelaarT' oftoplasmic o/din Dlesprassion with risk of tumor recurrence and death Methods: Cyelin D1 espression was studiad using immunohistochemistTy in patients (n 268) with pdmary, resactad, pathologic stage I NSCLC Both nuclear and cytoplasmic staining ware analyzad For both nuclear and cytoplasmic expression, the immunehistochemical staining was graded as 1. 2 and 3 based exclusively on the percentage of tumor tissue exhibiting positive staining in 0-5%. 6-50% and 51-100% respectively. Since cytoplasmic staining with o/clin D1 is not well standardr-'od, the adjacent tumor free brenellal epithelium (available for comparison in 70% of the cases) was also assessed for o/din D1 expressmen. Results: The meclan age of the patients was 66 years. The maJonty of patients were male (55%). had adenocarclnema (62%). wore treated with Iobectomy/pnaumonectomy (84%) and had stage IA disease (64%) The median follow-up tlma was 4 2 years Grada 3 nuelaar and cytoplasmic o/din D1 axpression was notad in 39 (15%) and 21g (81%) pafients respactJvely Nuelaar espression was not significa'ltly associated with tha probability of tumor rectJrrenca or patlant survival Howavar. pafients with grade 3 oftoplasmic espression of o/din D1 espadaneed significantly lass tumor recurrence and cancer related deaths than patiants with cytoplasmic grada 1/2 espression (p<0.05). After adjusting for age. gender, histology, stage and surgical procedure, patients with grade 3 cytoplasmic o/clin D1 espresslen remained at a significantly lower risk for tumor recurrence (HR= 0.45. 95%CI [0.25-0.83]). death from cancer (HR = 0.42. 95%CI [0.24-0.73]) and death from any cause (HR= 0.61. 95%CI [0.39-0.97]). Condiuslons: Based on our observations, cytoplasmic expressmen of o/clin DI. may serve as an independent prognostic factor in resectod stage I NSCLC. Thase rasults are similar to these noted by Rat.schiller at al (JCO. 2003) in their avaluation of o/din D1 espression in malignant and pramalignant lesions Absence of cytoplasmic o/din D1 expression may idenfify individuals at high risk for recurrence after therapeutic resection If cenfirmad in other prospective sedes, then o/din D1 may serva as a potanfial target for adjuvant tharapy in resactad NSCLC

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Detection of novel gensUc altsraUons In prelnvastve bronchial squamous cell carolnoma

C Gamis 1'2 J LeRiche 1'~. C MacAulay 1'~. S Lain 1'~. W Lain 1'2 ~BC

Cancer Research Center, Vancouver, Canada: 2Cancer Genebcs, Canada: 3Cancer tmagmg, Canada Despite advances in the detection and tTeatment of lung cancer the overall b year survival rata for those diagnosed in the late stages is bleak In order to provide new tTeatment strategies that will ulfimately result in improved survival it is important to understand the genetic alterations that drive this disease Due to the genomic instability associated with late stage tumors the understanding of disease progression can only be achieved by studying both preinvasive as well as early invas~vo tumors. In tnls study we focus on the identificafien of novel alterations in bronchial carcinoma m sltu (CIS). Objective: The objective of this study is to identify novel genefic altorafions in preinvaslve neopiesfic lung cancer. E.xperlmental Design: Using the Sub Mogebase Resolution Tiling (SMRT) Array we profiled 10 squamous CIS and 12 invas~vo squamous lung tumors for DNA copy number changes. This array con=sts of over 32.000 bactenal artificial chromosomes (BACs) that span the entire ganema With this filing c.overage the detection of multiple braakpoints within the same sample is accomplished in one axpenment Materials and Methods: Carcinoma in-sltu lesions detected by autoflourescanco brenchoscopy were identified and collected as part ofa chemopravention tnal Each sample was microdissectad for DNA extraction Signal intensity ratios obtained from the co4"~/bddizatlon of the CIS DNA labeled with Cyanine 5 and the Cyanlne 3 labeled normal reference DNA idonfifies the -100 kb sequences that have been amplified or deleted in the CIS samples. Using custom designed software all the samples probes were aligned enabling the detection of frequent alterations. The CIS samples were compared against the invasWe tumors to identify alterations specific to preinvaslvo lesmns. Results: Whole gonome profles were generated for 10 CIS and 12 invaslve squamous lung samples. The CIS lesions contained considerable fervor copy number changes than the invasiva tumor and the alterations in the preinvasive lesions were often more focal (usually less than a megabase) In the CIS samples, recurrent large, near whole arm. changes were detected on 3p. 3q.13q.17p. and 19q While novel submegabase genetic alterafions were idanfified on chromosomes 1p. 5p. 7q. 8p. 9p. 9q. 16p. and 1gq Conclusion: 13ling resolution arrays are comprehensive tools for DNA co W number profiling This is partioulady useful for analyzing preinvasive lesions as the alterations detected in these early stages are often submogabase in s~ze and may go undetected by traditional techniques. Using this approach we have idonfified recurrent novel gonefic alterations assoaatod with the oady stages of squamous (:ell lung cancer for further invost]gafion of lung cancer progression pathways.

Do hemoglobin (Hb) levels Influence outcomes of adjuvant chemotherapy (ACT) with clsplatlnNInorelblns In patients (pts) with completely resected non small cell lung cancer (NSCLC)9 The JBR.10 b'lal experience I Gauthiar ~ K Ding ~. T Winton ~. F Shepherd ~. R Livingston 2. D Johnson 3. J Rigas 4 . M Wi'ttehead ~. B Graham ~. L Seymour~ 1National Cancer

tnstttute of Canada C#mcal Trials Group, tOngston, ON, Canada: 2Southwest Oncotogy Group, SaatUe, WA, USA, 3Eastern Cooperat]ve Oncology Group, Nashwlle, TN, USA: '~Cancer and Leukemia Group B, C,h/cago, IL, USA Background Cisplafin induced anemia may correlate with adverse events (AEs). poor Quality of Li~ (QoL). decreased ACT dose intensity (DI). relapsefree survival (RFS) or overall survival (OS) Methods: The JBR10 thai demonstrated significantly longer survival (OS+RFS) with ACT (n = 243) versus observation (OBS) in = 239) in pts with resectod NSCLC 0Ninton. ASCO 2004). This esploratory analysis evaluated the predictive value of baseline (BL. all pts) and dunng treatment (DT. ACT pts only) Hb levels (modan. nadir. % drop) on OS and RFS when adjusted for prognostic factors (ago. gender, performance status (PS). disease stage. LDH. surgical procedure and histology). Hb was correlated with AEs (fat]~JO. clzziness, headache, dyspnea, ischsmia, venous thrombeambolic events). QoL (global. fafigue, shortness of breath (SOB). cogn~ve and physical functions). morbidity and ACT DI Results: BL Hb was significantly lower in women (p<00001). pts >61 yrs Co 0042) a n d p t s w i t h P S l v s P S 0(p 0008) BLHbwasnotprecictive 0og-rank) of RFS Co 0 936) or OS (p 0 273) However. there was a tTand to shorter OS (adjusted Cox model, p 0 1) when BL Hb <12g/dL: OS was shorter in pts >61 yrs Co 0019). man Co 0021). adenocarcinoma vs other histology Co= 0.006). N1 vs NO stage (p= 0.003) and in pts who underwent pnoumonectomy (p = 0.065). Lower BL Hb correlated with increased hespItalizat]on (ACT pts only. p = 0.04) and worse QoL COBS pts only. SOB. p = 0.003) with no impact on AEs or DI. Lower median DT Hb correlated only with increased fatigue Co= 0.02). There was a b-end to longer RFS Co= 0.08) in pts with lower nadr DT Hb and significantly longer OS and RFS (,o=0.01) in pts with maximum DT Hb drop >30%. even when the model was adjusted for DI Maximum DT Hb drop >30% also correlated with increased fatigue (hE. p 003:QoL. p 007) Conclusions: Lower BL and DT Hb levels seem associated with poorer QoL. fatlgua and increased hospitaliTafion There is atTend for shorter OS in pts with lower BL Hb levels Unespectadly. lower nadir DT Hb levels and higher°/= drops in DT Hb levels appear to predict for longer OS and RFS Further analyses exploring the latter fincings are currently being performed

N o n - s m a l l cell l u n g c a n c e r - E a r l y

Tuesday, 5 July 2005

disease (I-IliA) 10:00-17:00

IP-6161RamlflceUons of severe organ dysfunction In newly diagnosed petfants with small cell lung cancer K. Giordano. A. Jatol. A. Adjel. E. Creagan. G. Croghan. J. Jett. R. Marks. J. Molina. S. Okuno. R. Richardson. Mayo Clinic, Rochester, Minnesota, USA

Background Small c~l lung cancer (SC/C) is exquisitely sensitive to chemotherapy, and a survival advantage with Its use has boon well established. However, in the setting of severe organ dysfunction, where the risk of 1~catment essoclated adverse events is greater, the decision to b'oat a newly dagnosed SCLC patient is not straightforward. The goal of this study was to descnhe the dinical course of such pafients and to danfy whether there is a role for chemotherapy in this setting. Methods: Mecical records from SCLC patients who ware seen at a single tertiary medical institution from 1994 through 2002 were revie.ved Severe organ dysfun~on was defined as creatinine ~>3mg/dl. total bllirubin ~>3m~'cl. and/or platolet count ~<50x10 G per milliliter. Medical records from all newly dagnosed SCLC patients who mot these criteria were reviewed in depth. Results: Of 993 SCLC patients seen at our institution. 25 (2.5%) had severe organ dysfunction, as defined above. Eleven received chemotherapy; 11 cid not: and tTaatment information was unavailable for 3 patients Chemotherapy agents included o/clophosphamide, atoposida, paelItaxel. cisplatln and carbopiatln Initial dose reductions were made in 8 of the 11 patients due to underlying organ dysfuncfion After the initiation of chemotherapy, bilinJbin normalized in 3 patients and dedined considerably in 1 patient Median survival was 150 days for the chamotharapy-tTaated patients. and 10 days for those who did not receive chemotherapy (Sea Figure 1) COrlCJuslons: Those preliminary fincings suggest that. even in the presence of severe organ dysfunction, a subgroup of small coil lung cancer patients can tolerate chemotherapy, improve abnormal laboratory parameters, and live for several months. Further study of the role of chemotherapy in this group of patients is warranted.

Posters~Non-small 1.0

ceil l u n g c a n c e r -

0.B0.7-

~

~0.6-

$281

Methods: All lung patients with a pathological diagnosis of atypical ca~noid. typical carcinoid and neuroandocnne tumors were idenUfied from 1989 to 2004 from the British Columbia Cancer Agency Registry The pathology of all paUents was reviewed and reclassified Data was obtained regarding baseline characteristics, tTeatments and outcomes Results: We identified 181 patients with neursenddcrina and carcinoid tumors Pathology rsvie.~ has been completed on 158. samples to data Survival data will be available

l

0.9-

Early disease (HI/A)

+ chemotherapy

;> 0 . 5 o~ 0 . 4 -

- chemotherapy

0.30.20.10.0-

T 0

T

T

50

1

'

100

1

'

150

1 200

250

300

Survival (days) Figure 1: Survival curves for paUants who racalved chemotherapy (top line) and for palJents who rscaivad no chemotharapy (bottom line)

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Evaluating me Impact of neoadJuvant chsmo~srapy and surgery on quality of life (QL) In patients w l ~ early stage NSCLC: A prospective analysis of me GINEST project

R. Gralla I . M. Edelman 2. F. Detterbeck 3. T. Jahan 4. D. Loesch ~. S. Limentani 6. R. Govtndan z. C. ObasaJu u. L. Bless u. M. SocmskJ3. 1New York L ~ g Cancer

A#iance, New York, USA, 2University of Mary~and, Ba~rnore, USA, ~Mu/bdiscipiinary Thoracic Oncology Program, University of North Caro/ina, North CaKEina, USA, 4University of Ca/ifomia~an Francisco, San Francisco, USA, Central tnd/ana Cen~r Center, ln~anapo//s, USA: ~Caretma Hematology Onco/ogy and ~he B/umentha/ Cancer Center, Charlotte, USA, z Washington Un/vers~ ~. Louis, USA: eLrtly Research LaDs, tnCtanapo#s, USA Background: Significant

survival gains have been reported with both neoadjuvant and adjuvant approaches. However. these gans are modest and should be evaluated In terms of the Impact on QOL as wall as the added risks and t~ic~es associated with mult]modal~ treatment. Such analysis of the Impact of combined modaldy therapy on QL has rarely been prospectively analyzed. Methods: This analysis compares paUent1 declle), with a mean decrease of 44% In these patients. In this subgroup, an average of ,5 of the 9 LCSS parameters also declined: no single symptom was associated with the QL decline Worsening QL appeared more likely in pts having more than a Iobectomy or Stage III extent It did net appear to correlate with the chemotherapy regimen or baseline QL score Conclusions: 1) The majority of patients (78%) reported QL as improved or stable, when evaluated 6 months post-op after naoad]uvant tTeatment with gemcitabina-containing combinalJen chemotherapy: 2) prospective QL evaluation should be part of combined modal~ ~als. to characterize fully the impact of these approaches.

~ 1 8 ~ Re-dasslftcatlon of carclnold and nsurosndocrlns lung tumors: Patient treatment and outcomes C. He. R. O'Connor, N. Murray, J. Lasl~n, B. Melosky. Bt'~sh Columt~a

Canoar Agency, Vancouver, Canada Background: Pulmonary earcinoid tumors are uncommon malignancies '~lt to be denvad from neuroandochne Kulchltsky's calls within the bronchial mucosa Carcinoid tumors have been classified, according the revised WHO criteria in 1999. based on histological features asscolated wtth survival outcomes. We propose to revmw cases of pulmonary nouroendocnne tumors diagnosed ever the past 15 years at the British Columbia Cancer Agency. categorize them acoordeg to these criteria and assess outcomes.

n Median age Gender Male Female Stage Eady (1. II) Advanced (111.IV) Unlmown Treatment at diagnosis Surgery alone Raclat]on alone Chemotherapy alone Combined modality No treatment Utgrr~wn OUtcome Relapse or recurrence

Typical ca~noid

htypical ca~noid

Neureandocr|ne

74 61 5

38 64 ,5

46 64 5

32% 68%

39% 61%

63% 37%

71% 16% 13%

73% 29% 8%

33% 63% 4%

65% 5% 0 8,% 11% 11%

55% 11% 3% 1,5% 8% 8.%

33% 22% 17% 22% 2% 4%

13%

39%

59%

Conclusions: The majority of patients with typical and atypical carcinoid tumors wars clagnosed at an early stage and tTaated with single modality surgery As expected, with increasing histological risk. there is a nse in the rate of disease relapse. The rscogn~on of atypical caronoid as a more virulent subtype did not result in an increase in the use of chemotherapy however. the high relapse rate identifies the need Ibr an eff~ot]ve systemic therapy component of combined modal~ therapy. ~6~

Sldp medlastlnal nodal metastases in the IIIA/N2 non-small cell lung cancer

N. Ilic <. A. Pet]-Icovic2. S. Tanfara 3. S. Kotarac4. D. Afar ~. K. Miss G. N. Fdeta IIIc7. J. Banevlcu. 1University Surgical Hospital, Spirt, Crotatta,

2University Surgical Hosptal, Split, Croaba, 3C,/inicaJ Hospital Split, AnesL Dept., Croat~a, "~C/l~Cal Hosptal Spirt, Pu/rnology Dept., Croatta: 5C/lnlCal Hospita/ Spiit, Pu/mology DepL, CroaUa, ~CJinica/ HospitaJ Sprit, Pu/mo/ogy DepL, Croatia, ZCJinica/ Hospita/ Spiit, Onco/ogy Dept, CroaDa, e Univeraity Surgica/ Hospita/, Split, CroaUa Background: To study the incidence and charaotenstlca of medlastJnal nodal metastases w~hout N1 nodal involvement ('sl~pN2 metastases') in patients with resected plll/AtN2 nor. small cell lung cancer. Methods: A total of 322 NSCLC paUents who underwent Re surgical rsseot]en with a systemic medlastJnal nodal dlsseotJon In Ibur years time period (2000 2003) were retTospectlvaly reviwad The 8,5 patients (26%) at stage IIINN2 (pN2+) ware grouped accorcleg to their skip metastases status Patient's data were staUstically analyzed Results: Skip N2 metastases were found in 21 patients (25%) without N1 nodal involvement The postoperative survival rate for skip~12 deseasa was\almost the same as that for pN2 desaase with N1 nodal involvement The incidence of N2 metastases seemed to be more frequent in adanocarcinoma palJents Co >0.005). but sklpN2 metastases rate was slgnJficantelly higher Co >0.001) In squamous cell carcinoma patients. Altough skip metastases Involved more often upper mediast]nal lymphnodes and one station level, the difference was not found statistically significant (p > 0.227). Compllcat]ens rate showed no clffersnca between analyzed groups of patients. Conclusions: Sample mediastinal lymphadenootomy may not be appropriate In surgery for NSCLC. because skip metastases were found In 25% of patients without N1 nodal invevement Role of intmoperaUvely santinal node dissection has yet to be proven