systemic approaches for multifocal bronchioloalveolar ... filebronchioloalveolar carcinoma (bac) is...

Systemic Approaches for Multifocal Bronchioloalveolar Carcinoma: Is There an Appropriate Target?Published on Cancer Network (http://www.cancernetwork.com)

Systemic Approaches for Multifocal BronchioloalveolarCarcinoma: Is There an Appropriate Target?Review Article [1] | September 15, 2010 | Lung Cancer [2], Oncology Journal [3]By Benjamin P. Levy, MD [4], Alexander Drilon, MD [5], Liana Makarian, MD [6], Amit A. Patel, MD [7],and Michael L. Grossbard, MD [8]

Bronchioloalveolar carcinoma (BAC) is a subset of pulmonary adenocarcinoma characterized bydistinct and unique pathological, molecular, radiographic, and clinical features. While the incidenceof pure BAC is rare, comprising only 1% to 4% of non–small-cell lung cancer (NSCLC), mixedsubtypes (including BAC with focal invasion and adenocarcinoma with BAC features) represent asmuch as 20% of adenocarcinomas—and that figure may be increasing. Despite the longstandingrecognition of this entity, there is no established treatment paradigm for patients with multifocalBAC, resulting in competing approaches and treatment controversies. Current options for multifocalBAC include both surgery and systemic therapies. Unfortunately, prospective data on systemicapproaches are limited by study design and small patient numbers; there are only seven phase IIstudies involving four therapies. This article evaluates key characteristics of BAC, including thecurrent understanding of histopathology and tumor biology. In addition, it comprehensively reviewsthe systemic phase II studies in an attempt to clarify the therapeutic challenges in this disease. Italso includes the first proposed treatment paradigm that integrates both EGFR mutational status andthe sub-histologies, mucinous and nonmucinous BAC.

Bronchioloalveolar carcinoma (BAC) is a subset of pulmonary adenocarcinoma characterized bydistinct and unique pathological, molecular, radiographic, and clinical features. BAC was initiallydescribed by Malassez in 1876.[1] The term “bronchioloalveolar carcinoma” was coined by Liebow in1960 and identifies a well-differentiated tumor (adenocarcinoma) with neoplastic cells that spreadsalong alveoli without stromal reaction or invasion, and with preservation of alveolar architecture.[2]Although the pathological assessment of this tumor is still evolving, the current (1999) definition ofBAC by the World Health Organization (WHO) is restricted to lesions with a pure bronchioloalveolargrowth pattern in which there is no evidence of invasion of stroma, pleura, or lymphatic spaces.[3]The clinical applicability of this definition remains in question, considering that BAC most oftenpresents as admixed adenocarcinoma, with the clinical course of these tumors often differing fromthat of both pure BAC and adenocarcinoma. The incidence of pure BAC is rare, comprising only 1% to4% of non–small-cell lung cancer (NSCLC); however, these mixed subtypes, including BAC with focalinvasion and adenocarcinoma with BAC features, represent as much as 20% ofadenocarcinomas—and their frequency may be increasing.[4]

As BAC becomes a more recognized entity within the pathological continuum of adenocarcinoma,several controversies have emerged regarding the appropriate management of these tumors,especially those that represent multifocal or unresectable disease. First, while BAC features may beprognostic of improved survival, it remains unclear whether the percentage of BAC admixed within atumor is prognostic of outcome or predictive of therapy efficacy. For example, should thoseadenocarcinomas with greater BAC features be more conservatively managed than those with lessBAC? Second, there is an increasing awareness that two subtypes of BAC lesions exist: mucinous andnonmucinous.[5] Whether this pathological distinction is clinically relevant and whether it shouldguide management decisions remain unclear; these questions will be addressed in the discussionsection of this review. Finally, it has been demonstrated consistently that patients withadvanced-stage BAC have a disproportionately high response to the epidermal growth factorreceptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Recent phase III data inpatients with advanced NSCLC have demonstrated the EGFR mutation to be a reliable predictor ofresponse to TKIs in the front-line setting.[8] However, whether response to TKIs in BAC is exclusivelymediated by the EGFR mutation that is more frequently found in this subtype of tumor has yet to beprospectively evaluated. In this review, we attempt to evaluate these controversies as we discussthe key characteristics and current management of multifocal/unresectable BAC.

Histopathology of BAC of 16

http://www.cancernetwork.com/review-article

http://www.cancernetwork.com/lung-cancer

http://www.cancernetwork.com/oncology-journal

http://www.cancernetwork.com/authors/benjamin-p-levy-md

http://www.cancernetwork.com/authors/alexander-drilon-md

http://www.cancernetwork.com/authors/liana-makarian-md

http://www.cancernetwork.com/authors/amit-patel-md

http://www.cancernetwork.com/authors/michael-l-grossbard-md


The definition of BAC has evolved significantly over the years. In 1960, when Averill Liebow gave thetumor its current name, BAC was defined as a subtype of adenocarcinoma with four features:well-differentiated cytology, an origin distal to recognizable bronchi, a proclivity for lymphatic andaerogenous spread, and a tendency to grow across intact alveolar septa.[2] Liebow asserted,however, that this last feature was probably “imaginary,” implying that despite seemingly preservedarchitecture, invasion was a likely feature. In 1999, a major shift occurred in the WHO classification:BAC was redefined as a neoplasm that demonstrated pure lepidic growth with a lack of invasion ofstroma, blood vessels, or pleura.[3] The modification essentially restricted BAC to carcinoma in situand was maintained in the 2004 revision of the criteria.[5] Currently, tumors that are predominantlyBAC and that have areas of invasion are classified as “mixed subtype adenocarcinomas.”FIGURE 1

Histopathology of Mucinous vs Nonmucinous Bronchioloalveolar Carcinomas (BACs) (Hematoxylinand Eosin Stain, High-Power Magnification)

The WHO decision to reclassify BAC as a distinct pathological entity was largely based on seminalwork by Noguchi and colleagues, who examined 236 cases of small (less than 2 cm), surgicallyresected peripheral adenocarcinomas with mediastinal and pulmonary hilar lymph nodedissection.[9] Samples were separated into groups by histology, and patients were monitoredlongitudinally for survival. In patients with Noguchi type A histology (localized bronchioloalveolarcarcinoma [LBAC]) and type B histology (LBAC with foci of alveolar collapse), 0% showed lymph nodemetastasis, and survival was 100% at 5 years. However, among patients with Noguchi type Chistology (LBAC with active fibroblastic proliferation), 28% had lymph node metastasis, and 5-yearsurvival was 75%. Furthermore, patients with poorly differentiated adenocarcinoma (Noguchi type Dhistology) had a 52% 5-year survival rate. These results demonstrated that BAC had a distinctclinical course differing from that of adenocarcinoma and suggesting that this type of tumorwarranted its own classification.Two major subtypes of BAC are recognized by the WHO—mucinous BAC and nonmucinousBAC—along with a third category that represents a combination of the two (Figure 1).[5] Increasingevidence suggests that the major subtypes represent biologically distinct entities and underscoresthe necessity of distinguishing between the two in pathology specimens.[10]The nonmucinous variant is the clinically predominant subtype, occurring in 40% to 60% ofcases.[11] Nonmucinous BAC tumors tend to present grossly as solitary peripheral nodules and arehistologically composed of cuboidal or columnar cells with eosinophilic or clear cytoplasm, with orwithout vacuolization.[12,13] Nonmucinous BAC is recognized as comprising two cell types: Claracells, with apical snouts and PAS+ granules; and type 2 pneumocytes, often with eosinophilic nuclearinclusions. No clinical or prognostic difference has been ascribed to a predominance of either celltype.[13] Immunohistochemically, the nonmucinous variant of BAC exhibits a pattern similar to thatof conventional adenocarcinoma, with cytokeratin 7 (CK7) and thyroid transcription factor 1 (TTF1)positivity and cytokeratin 20 (CK20) negativity.[5] BAC with nonmucinous histology is more oftendependent on EGFR pathway mutations and is consequently more sensitive to EGFR-targetedtherapy.[10]

of 16

http://www.cancernetwork.com/sites/default/files/cn_import/1672699.png




Mucinous BAC occurs in anywhere from 25% to 50% of patients.[11,13] In contrast to nonmucinoustumors, mucinous BAC more commonly presents with extensive disease, manifested as multiplenodules or diffuse consolidation (pneumonic pattern). Because of the more advanced stage atdiagnosis, overall prognosis is poorer. Histologically, cells are tall and columnar with basal nuclei andabundant mucin.[12,13] The tumor is thought to arise from metaplastic goblet cells. In mucinousBAC, immunohistochemistry (IHC) results tend to be more variable: CK7 is usually positive, as innonmucinous BAC; however, CK20 is positive, and TTF1 is usually negative—or weak and patchy ifpositive. K-ras mutations are more commonly detected in mucinous BAC, likely accounting for therelative insensitivity of this subclass to EGFR-based treatments.[14]In patients with mixed subtype adenocarcinoma, the exact contribution of a bronchioloalveolarcomponent to prognosis has been the subject of debate. In the only Western study to address thisquestion, Ebright and colleagues reported no significant difference in survival between groups withpure BAC, BAC with focal invasion, and adenocarcinoma with BAC features.[15] The study did includepatients with pure BAC who had multifocal disease and pneumonic-type presentations; thesepatients had poorer expected outcomes. In contrast to the Ebright data, multiple previous Japanesestudies have provided evidence—in addition to that of Noguchi’s work—to support a favorableprognosis for specimens with large proportions of BAC and minimal invasion.[16-19] Terasaki andcolleagues grouped specimens according to increasing proportions of BAC and reported that groupswith either pure BAC or BAC with minimal areas of invasion were less likely to have pleural invasionor metastatic spread to lymph nodes or vasculature.[20] These studies suggest that tumors withhigher proportions of BAC may be prognostically more favorable.In light of the possible differences in clinical behavior between BAC with minimal invasion andtumors with larger invasive components, some authors have proposed that a category called“minimally invasive adenocarcinoma” be established in future classifications.[21] Sakurai andcolleagues demonstrated that the prognosis of BAC with stromal invasion limited to the area oftumor growth or the periphery of the tumor scar was equal to that seen in pure BAC.[18] Similarly,Yim and colleagues reported that the prognosis of patients with BAC and invasion of less than 5 mmwas equivalent to that of patients with BAC and no evidence of invasion.[19] In 2004, however, aconsensus definition of “minimally invasive” BAC was not recommended by the WHO panel on thebasis of lack of sufficient evidence.[22] As further data become available, it is possible that thiscategory may be formally separated, considering its increased incidence and clinical relevance.

Tumor Biology

FIGURE 2

Proposed Model of Tumorigenesis and Acquired Mutations

Recent investigations into the molecular biology of BAC have focused on its potential role as anintermediate stage in the development of lung adenocarcinoma (Figure 2).[4] In this model, stepwisemutations drive the transformation of the malignant clone through a series of histologies, fromadenomatous hyperplasia (AAH), to BAC, and finally invasive adenocarcinoma. The initial insult isthought to occur in the stem cell compartment in response to lung damage, and progenitor cellsknown as bronchioloalveolar stem cells, or BASCs, are recruited. Several mouse models havedemonstrated that mutations, including K-ras, p27kip, and PTEN, play a key role in the recruitmentand subsequent progression of BASCs to invasive disease.[23-25] At the cellular level, theproliferation gives rise to both Clara cells and type II pneumocytes that accumulate and transforminto what is recognized histologically as AAH.[4]The specific progression from AAH to BAC likely occurs through the accumulation of successivegenetic hits, including the allelic loss of 9p, 8q, and 17p.[26-28] However, it is important to note thatthis transformation gives rise to a specific biologic subset of BAC tumors. Molecular analyses haverevealed that K-ras mutations are commonly present in AAH, while EGFR mutations are infrequent,indicating that BACs and adenocarcinomas that are reliant on EGFR mutations probably do not arisefrom AAH.[29] The reliance of particular BAC subtypes on either K-ras or EGFR mutations is thoughtto be mutually exclusive[30,31] and serves to underscore biologic differences that support the

of 16





notion that BAC actually comprises two separate diseases.[32]Mucinous disease is more frequently associated with a variety of K-ras mutations, some specificallyoccurring on exon 1 (codon 12).[33,34]. In contrast, EGFR mutations and amplification or polysomyare associated almost exclusively with nonmucinous disease.[10,32] Furthermore, these EGFRmutations have been shown to co-exist with alterations in human epidermal growth factor receptor 2(HER2).[35,36] Nonmucinous disease is also likely to be found with a higher frequency in smokersthan is mucinous disease. Given these findings, further investigations will likely answer the questionof whether AAH is a precursor of mucinous disease exclusively.In the face of further molecular alterations, BAC is thought to transform eventually into frankadenocarcinoma. However, the exact sequence that drives this progression remains unknown. Theexpression of focal adhesion kinase (FAK) is significantly lower in BAC than in adenocarcinoma,indicating its potential role in the development of invasive disease.[37] Other genetic alterationshave also been shown to occur more commonly in adenocarcinoma than in BAC. These include lossof heterozygosity at 1p, 3p, 7p, and 18q, and increased levels of vascular endothelial growth factor(VEGF) expression.[27,29]As is the case for other tumors, the stepwise process of BAC tumorigenesis is complex, involvingmultiple pathways. Future investigations in this area hopefully will elucidate specific driver mutationsthat will serve to direct our approach to therapy at each step along the spectrum of disease.

Radiologic Features

BAC presents with a range of features that fall into three major radiographic patterns: solitarypulmonary nodules or masses (commonly termed ground glass opacities [GGO]), localizedconsolidation, and diffuse disease.[38-40] While each of these represents a distinct pattern that maybe reflective of clinical course, a combination of features may be present in a single patient.[40]Solitary nodules or masses are the most common BAC radiographic findings and are seen inapproximately 40% of patients.[41] Lesions vary from having well-defined to irregular borders andare composed of solid soft-tissue attenuation, ground glass attenuation, or a mixture of thetwo.[40,42] The proportion of each is thought to reflect biological differences within the tumor.[41]Nodules with a predominant GGO component correspond to lower Noguchi subtypes, suggestnonmucinous BAC, and are likely attributable to the lepidic growth pattern of the malignancy.[43-48]Mixed lesions are more frequently a feature of Noguchi type C tumors and suggest mixed subtypeadenocarcinoma.[42] An increasing solid component suggests higher biologic virulence andincreased likelihood of the tumor having an invasive component.[41]Localized consolidation accounts for 30% of cases and is believed to be typical of mucinous BAC[49].While diffuse parenchymal infiltration is often difficult to differentiate from pneumonic or otherinflammatory processes, certain radiologic features favor a diagnosis of BAC over pneumonia.[48]These include attenuation, stretching, and widening of branching air-filled bronchi within aconsolidation; and bulging of the interlobar fissure, which occurs secondary to mucin production andtumor swelling.[50] Mucin production is also thought to be the source of what was described by Imand colleagues as the “CT angiogram sign,” or visibly enhancing pulmonary vessels within aconsolidation.[51]Diffuse disease, which accounts for another 30% of cases, presents in various forms, includingmultinodular disease in one or more lobes, or a “crazy paving” pattern of extensive GGO and septalthickening.[47,48] Akira and colleagues reported that the combination of consolidation, satellitenodules, and remote areas of GGO is highly characteristic of BAC.[52]CT imaging represents the standard modality for assessment of the extent of disease. The utility offluorodeoxyglucose positron emission tomography (FDG-PET) in BAC also has been explored. Thestandardized uptake values (SUVs) of BAC are significantly lower than those seen in otheradenocarcinoma subtypes, probably due to BAC’s longer doubling times and slower rates ofproliferation.[53,54] However, multiple reports have established a high false-negative rate for PETimaging in the diagnosis of BAC.[55,56] In fact, only half of all cases have a maximum SUV of greaterthan 2.5, the commonly accepted threshold that distinguishes benign from malignant lungneoplasms.[42,57] Beyond diagnosis, FDG-PET may have more of a role in elucidating the biologicalaggressiveness and prognosis of established lesions—and thus in directing care. Raz and colleaguesdemonstrated that in patients with node-negative BAC, preoperative PET-avidity significantlypredicts lower long-term mortality compared with PET-negative disease.[4] Gandara and colleagueshave suggested that close observation with serial imaging may represent a viable alternative tosurgery in patients with PET-negative disease.[41]

of 16


In recent years, advances in MRI technology have prompted investigations into the potential of thismodality as a diagnostic tool for assessing BAC. Tanaka and colleagues described techniques such asSTIR (respiratory-triggered short inversion time [TI] inversion recovery) and high–b-valuediffusion-weighted imaging (DWI) that significantly differentiated pure BAC from otheradenocarcinoma subtypes.[58] Gadolinium-enhanced dynamic MRI also has been shown todifferentiate BAC from non-BAC lesions.[58,59] To date, however, the clinical role of MRI in theevaluation of solitary nodules remains limited.[60]In summary, BAC presents radiographically in several distinct patterns and morphologies thatultimately correlate with biologic differences related to histology and tumor aggressiveness. Atpresent, CT remains the standard for initial diagnostic evaluation. However, the utility of FDG-PET inestablishing the metabolic activity of disease, and its potential for determining the rate of growth oftumors, may result in its incorporation into future workup algorithms.

Clinical Course

The clinical presentation of BAC generally reflects the extent of disease. Most commonly, BACpresents as an asymptomatic process with 40% to 60% of cases incidentally diagnosed after patientshad undergone chest imaging for other indications.[61,62] Unlike with other histological subsets ofNSCLC, most patients with pure BAC present with surgically resectable disease—a reflection of thefact that pure BAC by definition is not associated with lymph node disease or distantmetastasis.[9,15,20,63,64] However, up to 80% of BAC cases present with admixedadenocarcinoma; of these tumors, 10% to 25% have mediastinal nodal involvement, with 5%demonstrating distant metastatic disease, suggesting that an initial surgical approach may not beindicated.[61]The clinical behavior of multifocal, unresectable BAC has been elucidated only from retrospectivestudies and is characterized by its tendency to present with intrathoracic metastasis, slow rate ofgrowth and progression, longer median survival, and increased prevalence in women andnonsmokers.[65] When symptomatic, patients most commonly present with cough, sputumproduction, chest pain, or dyspnea—and less frequently with fever, hemoptysis, weight loss, orfatigue. Patients with advanced diffuse bilateral pulmonary disease can present with severebronchorrhea and refractory hypoxemia from intrapulmonary shunting.[66] This clinical presentationis more commonly associated with the mucinous subset of BAC and can be mistaken for pneumoniaor pneumonitis. Death is characteristically secondary to respiratory failure in the setting of diffusepulmonary involvement infection, rather than resulting from the distant spread of cancer andinvolvement of other organ sites.[11] Metastases to sites outside the lungs are presumably due to aninvasive component that precludes a diagnosis of pure BAC.

Management

TABLE 1

Phase II Studies of Systemic Therapies for Multifocal BAC, Including Outcomes for Clinically RelevantSubgroups

Despite the longstanding recognition of this entity, there is no established treatment paradigm forpatients with multifocal BAC. This is largely due to the low incidence of pure BAC. However, otherfactors, including inconsistent pathological criteria and a scarcity of preclinical data (mouse lungcarcinomas that mimic classic human BAC histologically are nonexistent[67]) have led to knowledgegaps regarding the optimal treatment of this disease. Current options for multifocal BAC include bothsurgery and systemic therapies. Unfortunately, prospective data on both modalities are limited bystudy design and small patient numbers. In addition, the small phase II studies and retrospectiveseries that have been published on systemic approaches have yielded divergent results as a result of

of 16




differing radiographic criteria (WHO versus RECIST [Response Evaluation Criteria in Solid Tumours]),pathological assessments, and primary endpoints (Table 1).

Surgery

Although a comprehensive assessment of the surgical literature for BAC is beyond the scope of thisarticle, a brief discussion of this literature is warranted, given that surgical resection is the onlypotentially curative modality for this disease. Both prospective and retrospective surgical studieshave demonstrated that patients with completely resected limited stage (stage I/II) BAC have alonger survival as well as lower rates of recurrence and lymph node micrometastasis than dopatients with other subtypes of NSCLC.[68,69] In addition, further studies have suggested thatcompletely resected multifocal (stage IIIB or IV) BAC is associated with survival equivalent to that ofresected stage I NSCLC.[4] Specifically, Robert and colleagues and Furak and colleagues havereported 5-year survival rates of 64% and 82%, respectively, for completely resected multifocalBAC.[64,70] Based on the surgical series, it seems reasonable for fit patients with multifocal diseaseto be referred to an experienced surgeon for possible surgical resection. However, a definitivesurgical approach must take into account the potential presence of invasive areas ofadenocarcinoma admixed in the tumor, since it is impossible to differentiate pure BAC from admixedBAC by needle biopsy or frozen section.[71-73] In addition, mediastinal node involvement is found inup to 25% of admixed BAC, which suggests that these tumors may be more extensive than what isinitially demonstrated radiographically or pathologically.[61]

Systemic Treatment

Although BAC has traditionally been perceived as a chemoresistant disease, there have been onlytwo phase II studies evaluating the role of cytotoxic chemotherapy in BAC; each of these utilizedpaclitaxel. Experience with newer, third-generation agents such as pemetrexed (Alimta) orgemcitabine (Gemzar) has been described only in case reports or retrospective series; however,these agents have demonstrated competitive outcomes.[74,75] In the first prospective phase IIstudy evaluating cytotoxic chemotherapy (S9714), 58 patients with confirmed stage IIIB/IV BACreceived paclitaxel, 35 mg/m2/24 hours continuously infused for 96 hours every 3 weeks for aplanned 6 cycles.[76] The objective response rate was 14%, with stable disease achieved in 40% ofpatients. Median progression-free survival (PFS) and overall survival (OS) were 5 and 12 months,respectively. Retrospective evaluation demonstrated a marked difference in outcome between thedifferent histological subtypes; the nonmucinous subtype had an OS of 9 months, compared with OSfor the mucinous subtype and for adenocarcinoma with BAC of 17 and 18 months, respectively.Notably, there were no responses (0%) in patients with nonmucinous BAC, compared with a 19%response rate in patients with mucinous BAC. Unfortunately, this regimen resulted in unacceptablegrade 3-5 toxicity, including neutropenia (43%), febrile neutropenia (12%), infection (22%),pharyngitis (10%), and five treatment-related deaths; thus, the regimen was subsequentlyabandoned. In a second very small phase II study evaluating paclitaxel in multifocal BAC,[77] 19patients with unresectable stage III/IV or recurrent BAC received intravenous (IV) paclitaxel, 200mg/m2 over 3 hours, every 21 days until progression of disease or a maximum of 6 cycles. Thisstudy resulted in a disappointing response rate of only 11% and median PFS and OS of only 2.2 and8.6 months, respectively. The incidence of hematological grade 3-5 toxicity was less than thatreported in the earlier paclitaxel trial; the most common adverse effects were neutropenia (21%) andanemia and leucopenia (5.3% each).Retrospective analysis of early studies evaluating the role of EGFR TKIs in NSCLC demonstrateddisproportionate and often dramatic responses in those tumors classified as BAC.[78-80] Thisobservation has led to five phase II studies exploiting the EGFR pathway with either the TKIs erlotinib(Tarceva) and gefitinib (Iressa) or the monoclonal antibody cetuximab (Erbitux).In the first study, Kris and colleagues evaluated the role of erlotinib, 150 mg/d, in 69 patients withunresectable stage III/IV BAC (25% with “pure” BAC and 74% with adenocarcinoma with BACfeatures).[81] Results of this study demonstrated a partial response rate of 12% and a one-yearsurvival rate of 58%. Response rates correlated with both clinical and histological features; morerobust responses were seen in nonsmokers than in smokers (43% vs 37%) and in patients who hadadenocarcinoma with BAC features than in patients who had “pure” BAC (30% vs 7%).In a second trial evaluating the role of TKIs in BAC (S0126),[82] 136 patients (101 untreated, 35previously treated) received gefitinib, 500 mg/d until disease progression or prohibitive toxicity, withone-year survival selected as the primary endpoint. The overall response rates in the untreated and

of 16



previously treated groups were 17% and 9%, respectively. Median PFS was 4 months in theuntreated group and 3 months in the previously treated group. Interestingly, a similar median OSwas demonstrated in the two groups as well (13 months in the untreated group, 12 months in thepreviously treated group), and the one-year survival rate was 51% in both groups. An exploratorymultivariate analysis demonstrated that the clinical variables associated with improved OS includedfemale sex (hazard ratio [HR], 1.83; P=.063), the development of rash (HR, 2.41; P=.01), and aperformance status of 1 or less (HR, 2.07; P=.006). Although the dose of gefitinib used wasconsidered to be double the normal dose, the regimen was reasonably well tolerated; the grade 3-4toxicities seen included rash (12%), diarrhea (21%), fatigue (5%), nausea (4%), and elevatedtransaminase levels (6%).Two retrospective studies were subsequently published (in abstract form only) that importantlysought to identify histological and molecular predictors of outcome in the S0126 study. In abiomarker analysis of this study, Hirsch and colleagues showed that the presence of EGFR-activatingmutations, increased EGFR protein expression as demonstrated by IHC, and increased gene copy asdemonstrated by fluorescence in situ hybridization (FISH) were each predictive of response togefitinib; however, only the latter two markers were associated with increased patient survival.[83]In a second analysis, Franklin and colleagues were able to demonstrate drastically differentoutcomes and responses to gefitinib for different sub-histologies.[84] The rate of response togefitinib in nonmucinous BAC was 30%, with stable disease achieved in an additional 40%, comparedwith a 0% response rate and 0% achievement of stable disease in mucinous BAC. In addition,nonmucinous BAC was associated with significantly longer survival (HR, 2.85; P=.0030). It is likelythat the differing molecular profiles of these two sub-histologies, as reflected in the fact that EGFRmutations are exclusively found in nonmucinous BAC, were responsible for the discrepant responsesseen with gefinitib in this trial.Following this study, Miller and colleagues sought to determine the activity of erlotinib, 150 mg, in101 patients with either pure BAC (n=12) or adenocarcinoma, BAC subtype (n=89); the primaryendpoint was response rate as determined by RECIST criteria.[85] Patients continued treatment untildisease progression began or toxicity reached unacceptable levels. In this study, 25% of patients(n=26) had received prior chemotherapy one time. Erlotinib treatment resulted in an overallresponse rate of 22%, a median PFS of 4 months, and a median OS of 17 months. As in the S0126trial, it was demonstrated that prior cytotoxic chemotherapy had no effect on clinical outcomes;similar response rates, PFS, and OS were seen in the untreated and previously treated groups(response rates, 27% and 21%, respectively; PFS, 4 months in both groups; OS, 16 months and 17months, respectively). Clinical variables associated with improved survival included prior resectionfor BAC (P=.02), performance status of 90 or greater (P < .01), and no prior weight loss (P < .01). Inaddition, a correlative molecular analysis was performed on 82 of the 101 patients, including EGFRmutation testing by polymerase chain reaction (PCR), chromogenic in situ hybridization (CISH), IHC,and K-ras mutation testing by PCR. While the response rate and PFS were significantly morepronounced in patients who harbored the EGFR mutation than in those with EGFR wild type(response rate, 83% vs 7%, P < .01; PFS, 13 months vs 2 months, P < .01), there was no significantdifference in OS between these two groups (23 months vs 17 months, P=.65). Not surprisingly,patients with K-ras mutations had a response rate of 0%. A multivariate analysis performed on thesemolecular predictors demonstrated the EGFR mutation to be the strongest predictor of both responserate and PFS (P < .001).In the final study evaluating TKIs in BAC, 88 chemotherapy-nave patients with advanced or recurrentBAC were treated with gefinitib, 250 mg, until disease progression began or toxicity reachedunacceptable levels (IFCT-0401).[86] The primary objective of this study was assessment of diseasecontrol rate (objective response + stable disease) at 3 months, using WHO criteria for response.Treatment with gefitinib resulted in a 3-month disease control rate of 29.4% and median PFS and OSof 2.9 months and 13.2 months, respectively. In a multivariate analysis, clinical characteristicsconsistently associated with improved clinical outcomes (3-month disease control rate, PFS, and OS)were a low respiratory symptom score (RSS) at inclusion (RSS less than 9), nonmucinous BAC, anddevelopment of rash during treatment. More specifically, median PFS and OS were significantly anddramatically prolonged in patients with nonmucinous BAC compared with patients with mucinousBAC (PFS, 11.3 months vs 2.6 months, P=.002; OS, 32.7 months vs 10.1 months, P=.0007).Treatment was generally well tolerated, with grade 3-4 toxicity limited to rash (4.6%), asthenia(1.1%), pulmonary symptoms (1.1%), and transaminitis (2.3%).In an alternative approach to targeting of the EGFR pathway in advanced BAC, 41 highly pretreatedpatients with histologically confirmed BAC or adenocarcinoma with BAC features received a loading

of 16


dose of cetuximab, 400 mg/m2, followed by weekly cetuximab, 250 mg/m2 until diseaseprogression.[87] Most patients in this cohort had received some form of prior therapy(chemotherapy, 24%; radiotherapy, 5%; and surgery, 71%). The primary endpoint of response ratewas achieved in 7% of patients, suggesting marginal clinical activity of cetuximab compared withgefitinib or erlotinib. Median PFS and OS were 3.2 months and 13 months, respectively. Molecularanalysis was performed on 33 patient samples, and of the 9 patients with the EGFR mutation, only 1had an objective response. Interestingly, 2 of 8 patients with the K-ras mutation had an objectiveresponse. Skin rash was the most common toxicity (any grade, 71%; grade of 3 or higher, 15%), andhypomagnesemia was noted in 26%.In summary, while the incidence of BAC is increasing, there remains a lack of prospective data onagents that are potentially clinically active against this disease. Thus far, seven phase II studies, twoutilizing paclitaxel and five exploiting the EGFR pathway (with erlotinib, gefitinib, or cetuximab),have generated varying response rates and survival times. Importantly, most of these trials haveidentified both molecular and clinical predictors that are associated with improved outcomes; thesefindings demonstrate the need to further define the complex pathophysiology of BAC in this era oftargeted therapy. Many outstanding questions remain regarding the optimal treatment of thisdisease.

Discussion

With a firmer understanding of the molecular-genetic landscape of lung cancer, multiple advanceshave recently been made in the treatment of NSCLC, resulting in the development of effective noveltargeted and chemotherapeutic agents. Whether these strategies can cross over into the treatmentparadigm for BAC has yet to be validated prospectively, and a consideration of these strategieshighlights several therapeutic challenges in this disease. Perhaps one of the most salient issues inthe treatment of NSLCL is the importance of EGFR testing in those patients more likely to harbor themutation based on clinical criteria (Asian, female, nonsmoker, adenocarcinoma). Recently, four largephase III trials comparing front-line gefitinib to platinum chemotherapy in advanced NSLCLdemonstrated a dramatically higher response rate and greater PFS with gefitinib in those patientsharboring the EGFR mutation.[6-8] Data from these trials and the high response rate demonstratedin the phase II trials reviewed here constitutes strong evidence supporting front-line treatment with aTKI in patients with BAC who harbor the EGFR mutation.Reference GuideTherapeutic Agents

Mentioned in This ArticleCetuximab (Erbitux)

Erlotinib (Tarceva)

Gefitinib (Iressa)

Gemcitabine (Gemzar)

Paclitaxel

Pemetrexed (Alimta)

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

of 16


However, the approach to those patients whose BAC tumors are EGFR wild type—or in the commonscenario in which mutational status is unknown or untested—remains a therapeutic dilemma.Perhaps the first question in these clinical scenarios is whether treatment with a TKI should beabandoned altogether. To evaluate this question, two points need to be considered. First,retrospective assessment from the study performed by Miller and colleagues demonstrated aresponse rate of 8% in those patients with wild-type EGFR who were treated with erlotinib,[85] whichis not dramatically different from the rates demonstrated in the studies by West and Scagliotii thatused IV paclitaxel (14% and 11%, respectively).[76,77] These results suggest that those patientswith no detectable EGFR mutation may still benefit from treatment with a TKI; moreover, this notionis supported by several lines of research that demonstrate that EGFR wild type tumors may rely onalternate EGFR signaling pathways.[88] This concept has subsequently been reinforced in two largephase III studies demonstrating the clinical utility of erlotinib in the second-line and maintenancesettings, independent of mutational status.[89,90]The second point that needs to be addressed is the role of cytotoxic chemotherapy in BAC. While it isestablished that platinum chemotherapy remains a front-line standard treatment for fit patients withadvanced NSCLC, there has not yet been a prospective study evaluating platinum chemotherapy inBAC or admixed BAC with adenocarcinoma. Interestingly, retrospective data from the sentinel ECOG1594 study demonstrated a response rate of 6% to platinum chemotherapy in those patients withBAC.[74] Again, this is a rate not that different from the rates seen in the patients with EGFR wildtype tumors who were treated with erlotinib in the trial by Miller (8%), or the rates in the two studiesin which IV paclitaxel was used (14% and 11%). While the data are limited, it seems reasonable,based on the similar response rates, to consider erlotinib, platinum doublet chemotherapy, or singleagent chemotherapy as first-line treatment options for those patients with unresectable BAC with anegative or unknown mutation status. Fortunately, further histological discrimination of these tumorsmay help guide treatment decisions and may introduce watchful waiting into the treatmentparadigm.Perhaps as important as the EGFR mutation assessment in the treatment of these patients is thepathological distinction of mucinous vs nonmucinous BAC. It has been consistently demonstrated inthe trials reviewed here that these two histological subtypes have divergent clinical outcomes thatmay be reflective of their molecular signatures. The differing responses of these sub-histologies topaclitaxel are supported by the preclinical finding that human lung cancer cell lines that harbor EGFRmutations, which appear to be found exclusively in nonmucinous BAC, have pronounced resistanceto both cisplatin and taxane chemotherapy.[91] Similarly, both the SWOG 0216 and IFTC-0401 trialsdemonstrated marked disparities in outcomes (response rate, PFS, and OS) between mucinous andnonmucinous BAC treated with gefitinib. This was most dramatically demonstrated in the morerecent IFTC-0401 trial, in which the OS in patients with nonmucinous BAC was 32.7 months,compared with 10.1 months in patients with mucinous BAC. These results suggest that the presenceof the EGFR mutation that is found exclusively in nonmucinous histologies may be the underlying

predictor of the divergent clinical outcomes.FIGURE 3

Unresectable/Multifocal BAC Treatment Algorithm

Given the selective responses to both TKIs and paclitaxel and the disparate clinical outcomesdemonstrated with these agents, the assessment of both EGFR mutation status and sub-histologyshould be integrated into the treatment paradigm for patients with unresectable BAC. In making thisrecommendation, we recognize that prospective data remain limited and that these pathologicalassessments are not yet standardized. While treatment for patients with tumors that are EGFRmutation–positive seems straightforward, the authors believe that those patients with tumors thatare EGFR wild type or of unknown mutation status should be further subdivided into those withmucinous and nonmucinous disease (Figure 3). For patients with unresectable mucinous BAC, webelieve platinum doublet chemotherapy should be utilized in those patients who are candidates,despite the lack of prospective evidence. Although BAC is commonly perceived as an indolent tumor,

of 16





the data suggest that this may be true only for nonmucinious histologies or admixed variants (seebelow); thus, mucinous BAC should be treated as aggressively as possible since the median survivalfor that entity is just over one year in most series. Treatment of nonmucinous histologies that are EGFR wild type or of unknown mutation remains a therapeutic challenge. The authors believe thaterlotinib, single agent or platinum doublet chemotherapy, as well watchful waiting all are options forconsideration, and that the selection should be contingent on such factors as clinical presentationand performance status.Finally, considering that up to 80% of BAC presents admixed with adenocarcinoma, thispathologically defined subtype warrants discussion. While the surgical literature demonstrates thatthe presence of any BAC feature predicts improved survival, compared stage-for-stage with pureadenocarcinoma,[9,20,64,92-94] it is still unknown whether a higher proportion of BAC in anadmixed tumor portends a better outcome than a lower proportion of BAC. As with the literature onpure BAC, there are very few prospective data addressing this subtype. Although treatment shouldbe a factor in the potentially indolent nature of this histological subtype, it is our recommendationthat treatment be consistent with that of advanced stage adenocarcinoma, per NationalComprehensive Cancer Network guidelines.As we usher in a new era of research into the specific signaling pathways and moleculardeterminants of cancer growth, we look forward to the identification of additional biomarkers thatwill result in more targeted approaches to the treatment of BAC. It is our hope that focused researchinto this subtype of adenocarcinoma will result in advances similar to those seen recently in NSCLCand will clarify the many outstanding questions related to the treatment of this disease.Financial Disclosure: Dr. Levy receives speaker’s honoraria from Eli Lilly, Genentech, andResponse Genetics. Drs. Drilon, Makarian, Patel, and Grossbard have no significant financial interestsor other relationships to disclose. References: References

1. Barkley JE, Green MR. Bronchioloalveolar carcinoma. J Clin Oncol. 1996;14:2377-86.

2. Liebow A. Bronchiolo-alveolar carcinoma. Adv Intern Med. 1960;10:329-58.

3. Travis WD, Colby TV, Corrin B, et al., editors. Histological typing of lung and pleural tumors. 3rded. Berlin: Springer-Verlag; 1999.

4. Raz DJ, He B, Rosell R, Jablons DM. Bronchioloalveolar carcinoma: a review. Clin Lung Cancer.2006;7:313-22.

5. Travis WD, editor. World Health Organization, International Agency for Research on Cancer,international Association for the Study of Lung Cancer, International Academy of Pathology.Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon Oxford: IARC Press,Oxford University Press; 2004.

6. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonaryadenocarcinoma. N Engl J Med. 2009;361:947-57.

7. Inoue A, Kobayashi K, Usui K, et al. First-line gefitinib for patients with advanced non-small-celllung cancer harboring epidermal growth factor receptor mutations without indication forchemotherapy. J Clin Oncol. 2009;27:1394-400.

8. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients withnon-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor(WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-8.

9. Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologiccharacteristics and prognosis. Cancer. 1995;75:2844-52.

10. Garfield DH, Cadranel J. The importance of distinguishing mucinous and nonmucinous

of 16


bronchioloalveolar carcinomas. Lung. 2009;187:207-8.

11.West H. Emerging approaches to advanced bronchioloalveolar carcinoma. Curr Treat OptionsOncol. 2006;7:69-76.

12. Moran CA. Pulmonary adenocarcinoma: the expanding spectrum of histologic variants. ArchPathol Lab Med. 2006;130:958-62.

13. Yousem SA, Beasley MB. Bronchioloalveolar carcinoma: a review of current concepts andevolving issues. Arch Pathol Lab Med. 2007;131:1027-32.

14. Finberg KE, Sequist LV, Joshi VA, et al. Mucinous differentiation correlates with absence of EGFRmutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn. 2007;9:320-6.

15. Ebright MI, Zakowski MF, Martin J, et al. Clinical pattern and pathologic stage but not histologicfeatures predict outcome for bronchioloalveolar carcinoma. Ann Thorac Surg. 2002;74:1640-6;discussion 6-7.

16. Yokose T, Suzuki K, Nagai K, et al. Favorable and unfavorable morphological prognostic factors inperipheral adenocarcinoma of the lung 3 cm or less in diameter. Lung Cancer. 2000;29:179-88.

17. Suzuki K, Yokose T, Yoshida J, et al. Prognostic significance of the size of central fibrosis inperipheral adenocarcinoma of the lung. Ann Thorac Surg. 2000;69:893-7.

18. Sakurai H, Maeshima A, Watanabe S, et al. Grade of stromal invasion in small adenocarcinoma ofthe lung: histopathological minimal invasion and prognosis. Am J Surg Pathol. 2004;28:198-206.

19. Yim J, Zhu LC, Chiriboga L, et al. Histologic features are important prognostic indicators in earlystages lung adenocarcinomas. Mod Pathol. 2007;20:233-41.

20. Terasaki H, Niki T, Matsuno Y, et al. Lung adenocarcinoma with mixed bronchioloalveolar andinvasive components: clinicopathological features, subclassification by extent of invasive foci, andimmunohistochemical characterization. Am J Surg Pathol. 2003;27:937-51.

21. Dacic S. Minimally invasive adenocarcinomas of the lung. Adv Anat Pathol. 2009;16:166-71.

22. Travis WD GK, Franklin W. Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinicalimportance and research relevance of the 2004 World Health Organization pathologic criteria. JournThorac Oncol. 2006;1:S13-S9.

23. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normallung and lung cancer. Cell. 2005;121:823-35.

24. Besson A, Hwang HC, Cicero S, et al. Discovery of an oncogenic activity in p27Kip1 that causesstem cell expansion and a multiple tumor phenotype. Genes Dev. 2007;21:1731-46.

25. Yanagi S, Kishimoto H, Kawahara K, et al. PTEN controls lung morphogenesis, bronchioalveolarstem cells, and onset of lung adenocarcinomas in mice. J Clin Invest. 2007; 117:2929-40.

26. Dacic S, Finkelstein SD, Yousem SA. Clonal selection of adenocarcinoma of the lung asdetermined by loss of heterozygosity. Exp Mol Pathol. 2005;78:135-9.

27. Sasatomi E, Johnson LR, Aldeeb DN, et al. Genetic profile of cumulative mutational damageassociated with early pulmonary adenocarcinoma: bronchioloalveolar carcinoma vs stage I invasiveadenocarcinoma. Am J Surg Pathol. 2004;28:1280-8.

28. Yamasaki M, Takeshima Y, Fujii S, et al. Correlation between morphological heterogeneity andgenetic alteration within one tumor in adenocarcinomas of the lung. Pathol Int. 2000;50:891-6.

of 16


29. Wislez M, Beer DG, Wistuba I, et al. Molecular biology, genomics, and proteomics inbronchioloalveolar carcinoma. J Thorac Oncol. 2006;1(9 Suppl):S8-12.

30. Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc.2009;6:201-5.

31. Bianchi F, Nicassio F, Di Fiore PP. Unbiased vs biased approaches to the identification of cancersignatures: the case of lung cancer. Cell Cycle. 2008;7:729-34.

32. Garfield DH, Cadranel J, West HL. Bronchioloalveolar carcinoma: the case for two diseases. ClinLung Cancer. 2008;9:24-9.

33. Marchetti A, Martella C, Felicioni L, et al. EGFR mutations in non-small-cell lung cancer: analysisof a large series of cases and development of a rapid and sensitive method for diagnostic screeningwith potential implications on pharmacologic treatment. J Clin Oncol. 2005;23:857-65.

34. Sakuma Y, Matsukuma S, Yoshihara M, et al. Distinctive evaluation of nonmucinous andmucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses forJapanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and genemutations. Am J Clin Pathol. 2007;128:100-8.

35. Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by fluorescentin situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximaband chemotherapy. J Clin Oncol. 2008;26:3351-7.

36. Erman M, Grunenwald D, Penault-Llorca F, et al. Epidermal growth factor receptor, HER-2/neuand related pathways in lung adenocarcinomas with bronchioloalveolar features. Lung Cancer.2005;47:315-23.

37. Wang C, Yang R, Yue D, Zhang Z. Expression of FAK and PTEN in bronchioloalveolar carcinomaand lung adenocarcinoma. Lung. 2009;187:104-9.

38. Trigaux JP, Gevenois PA, Goncette L, et al. Bronchioloalveolar carcinoma: computed tomographyfindings. Eur Respir J. 1996;9:11-6.

39. Bonomo L, Storto ML, Ciccotosto C, et al. Bronchioloalveolar carcinoma of the lung. Eur Radiol.1998;8:996-1001.

40. Sabloff BS, Truong MT, Wistuba II, Erasmus JJ. Bronchioalveolar cell carcinoma: radiologicappearance and dilemmas in the assessment of response. Clin Lung Cancer. 2004;6:108-12.

41. Gandara DR, Aberle D, Lau D, et al. Radiographic imaging of bronchioloalveolar carcinoma:screening, patterns of presentation and response assessment. J Thorac Oncol. 2006;1(9Suppl):S20-6.

42. Raz DJ, Kim JY, Jablons DM. Diagnosis and treatment of bronchioloalveolar carcinoma. Curr OpinPulm Med. 2007;13:290-6.

43. Kuriyama K, Seto M, Kasugai T, et al. Ground-glass opacity on thin-section CT: value indifferentiating subtypes of adenocarcinoma of the lung. AJR Am J Roentgenol. 1999;173:465-9.

44. Matsugama H. Proportion of ground-glass opacity on high-resolution compted tomography inclinical T1 N0 M0 adenocarcinoma of the lung a predictor of lymph node metastasis. J ThoracicCardiovasc Surg. 2002;124:221-2.

45. Nakata M, Sawada S, Saeki H, et al. Prospective study of thoracoscopic limited resection forground-glass opacity selected by computed tomography. Ann Thorac Surg. 2003;75:1601-5;discussion 5-6.

of 16


46. Nakamura H, Saji H, Ogata A, et al. Lung cancer patients showing pure ground-glass opacity oncomputed tomography are good candidates for wedge resection. Lung Cancer. 2004;44:61-8.

47. Travis WD, Garg K, Franklin WA, et al. Evolving concepts in the pathology and computedtomography imaging of lung adenocarcinoma and bronchioloalveolar carcinoma. J Clin Oncol.2005;23:3279-87.

48. Patsios D, Roberts HC, Paul NS, et al. Pictorial review of the many faces of bronchioloalveolar cellcarcinoma. Br J Radiol. 2007;80:1015-23.

49. Shah RM, Balsara G, Webster M, Friedman AC. Bronchioloalveolar cell carcinoma: impact ofhistology on dominant CT pattern. J Thorac Imaging. 2000;15:180-6.

50. Jung JI, Kim H, Park SH, et al. CT differentiation of pneumonic-type bronchioloalveolar cellcarcinoma and infectious pneumonia. Br J Radiol. 2001;74:490-4.

51. Im JG, Han MC, Yu EJ, et al. Lobar bronchioloalveolar carcinoma: “angiogram sign” on CT scans. Radiology. 1990;176:749-53.

52. Akira M, Atagi S, Kawahara M, et al. High-resolution CT findings of diffuse bronchioloalveolarcarcinoma in 38 patients. AJR Am J Roentgenol. 1999;173:1623-9.

53. Aquino SL, Halpern EF, Kuester LB, Fischman AJ. FDG-PET and CT features of non-small cell lungcancer based on tumor type. Int J Mol Med. 2007;19:495-9.

54. Sun JS, Park KJ, Sheen SS, et al. Clinical usefulness of the fluorodeoxyglucose (FDG)-PET maximalstandardized uptake value (SUV) in combination with CT features for the differentiation ofadenocarcinoma with a bronchioloalveolar carcinoma from other subtypes of non-small cell lungcancers. Lung Cancer. 2009;66:205-10.

55. Heyneman LE, Patz EF. PET imaging in patients with bronchioloalveolar cell carcinoma. LungCancer. 2002;38:261-6.

56. Yap CS, Schiepers C, Fishbein MC, et al. FDG-PET imaging in lung cancer: how sensitive is it forbronchioloalveolar carcinoma? Eur J Nucl Med Mol Imaging. 2002;29:1166-73.

57. Wang Y. FDG-PET in bronchial alveolar carcinoma. Chinese-German J Clin Oncol. 2006;5:P54-P7.

58. Tanaka R, Horikoshi H, Nakazato Y, et al. Magnetic resonance imaging in peripheral lungadenocarcinoma: correlation with histopathologic features. J Thorac Imaging. 2009;24:4-9.

59. Ohno Y, Hatabu H, Takenaka D, et al. Dynamic MR imaging: value of differentiating subtypes ofperipheral small adenocarcinoma of the lung. Eur J Radiol. 2004;52:144-50.

60. Fujimoto K. Usefulness of contrast-enhanced magnetic resonance imaging for evaluating solitarypulmonary nodules. Cancer Imaging. 2008;8:36-44.

61. Dumont P, Gasser B, Rouge C, et al. Bronchoalveolar carcinoma: histopathologic study ofevolution in a series of 105 surgically treated patients. Chest. 1998;113:391-5.

62. Carretta A, Canneto B, Calori G, et al. Evaluation of radiological and pathological prognosticfactors in surgically-treated patients with bronchoalveolar carcinoma. Eur J CardiothoracSurg. 2001;20:367-71.

63. Liu YY, Chen YM, Huang MH, Perng RP. Prognosis and recurrent patterns in bronchioloalveolarcarcinoma. Chest. 2000;118:940-7.

64. Furak J, Trojan I, Szoke T, et al. Bronchioloalveolar lung cancer: occurrence, surgical treatment

of 16


and survival. Eur J Cardiothorac Surg. 2003;23:818-23.

65. Laskin J SA, Johnson D. Redefining Bronchioloalveolar Carcinoma. Seminars in Oncology.2005;32:329-35.

66. Barlesi F, Doddoli C, Thomas P, et al. Bilateral bronchioloalveolar lung carcinoma: is there a placefor palliative pneumonectomy? Eur J Cardiothorac Surg. 2001;20:1113-6.

67. Christiani DC, Pao W, DeMartini JC, et al. BAC consensus conference, November 4-6, 2004:epidemiology, pathogenesis, and preclinical models. J Thorac Oncol. 2006;1(9 Suppl):S2-7.

68. Regnard JF, Santelmo N, Romdhani N, et al. Bronchioloalveolar lung carcinoma: results of surgicaltreatment and prognostic factors. Chest. 1998;114:45-50.

69. Rena O, Papalia E, Ruffini E, et al. Stage I pure bronchioloalveolar carcinoma: recurrences,survival and comparison with adenocarcinoma of the lung. Eur J Cardiothorac Surg. 2003;23:409-14.

70. Roberts PF, Straznicka M, Lara PN, et al. Resection of multifocal non-small cell lung cancer whenthe bronchioloalveolar subtype is involved. J Thorac Cardiovasc Surg. 2003;126:1597-602.

71. Atkins KA. The diagnosis of bronchioloalveolar carcinoma by cytologic means. Am J ClinPathol. 2004;122:14-6.

72. Marchevsky AM, Changsri C, Gupta I, et al. Frozen section diagnoses of small pulmonary nodules:accuracy and clinical implications. Ann Thorac Surg. 2004;78:1755-9.

73. Miller DL, Rowland CM, Deschamps C, et al. Surgical treatment of non-small cell lung cancer 1 cmor less in diameter. Ann Thorac Surg. 2002;73:1545-50; discussion 50-1.

74. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of fourchemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-8.

75. Duruisseaux M, Cadranel J, Biron E, et al. Major and prolonged response to pemetrexed in twocases of lung adenocarcinoma with bronchioloalveolar carcinoma features. Lung Cancer.2009;65:385-7.

76. West HL, Crowley JJ, Vance RB, et al. Advanced bronchioloalveolar carcinoma: a phase II trial ofpaclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study. Ann Oncol.2005;16:1076-80.

77. Scagliotti GV, Smit E, Bosquee L, et al. A phase II study of paclitaxel in advancedbronchioloalveolar carcinoma (EORTC trial 08956). Lung Cancer. 2005;50:91-6.

78. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib forpreviously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003;21:2237-46.

79. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptorunderlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med.2004;350:2129-39.

80. Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar pathologic subtype and smoking historypredict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol. 2004;22:1103-9.

81. Kris MG, Sandler A, Miller M, et al. Cigarette smoking history predicts sensitivity to erlotinib:results of a phase II trial in patients with bronchioloalveolar carcinoma (BAC) [abstract]. J Clin Oncol.2004;145(July 15 Suppl):7062.

82. West HL, Franklin WA, McCoy J, et al. Gefitinib therapy in advanced bronchioloalveolar

of 16


carcinoma: Southwest Oncology Group Study S0126. J Clin Oncol. 2006;24:1807-13.

83. Hirsch FR GD, McCoy J. Increased EGFR gene copy number detected by FISH is associated withincreased sensitivity to gefitinib in patients in patients with bronchioloaveolar carcinoma(BAC)(S0126). J Clin Oncol. 2005;24(628s).

84. Franklin WA CK, Gumerlock PH. Association between activation of ErbB pathway genes andsurvival following gefitinib treatment in advanced BAC (SWOG 0126). Proc Amer Soc Cli Oncol.2004;23(620s).

85. Miller VA, Riely GJ, Zakowski MF, et al. Molecular characteristics of bronchioloalveolar carcinomaand adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J ClinOncol. 2008;26:1472-8.

86. Cadranel J, Quoix E, Baudrin L, et al. IFCT-0401 Trial: a phase II study of gefitinib administered asfirst-line treatment in advanced adenocarcinoma with bronchioloalveolar carcinoma subtype. JThorac Oncol. 2009;4:1126-35.

87. Ramalingam S, Lee J, Belani CP, et al. Cetuximab for the treatment of advancedbronchioloalveolar carcinoma (BAC): an Eastern Cooperative Oncology Group phase II study (ECOG1504). J Clin Oncol. 2010;28(15s).

88. Bunn PA, Jr., Dziadziuszko R, Varella-Garcia M, et al. Biological markers for non-small cell lungcancer patient selection for epidermal growth factor receptor tyrosine kinase inhibitor therapy. ClinCancer Res. 2006;12:3652-6.

89. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-celllung cancer. N Engl J Med. 2005;353:123-32.

90. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advancednon-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. LancetOncol. 2010;11:521-9.

91. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung canceractivate anti-apoptotic pathways. Science. 2004;305:1163-7.

92. Higashiyama M, Kodama K, Yokouchi H, et al. Prognostic value of bronchiolo-alveolar carcinomacomponent of small lung adenocarcinoma. Ann Thorac Surg. 1999;68:2069-73.

93. Koga T, Hashimoto S, Sugio K, et al. Lung adenocarcinoma with bronchioloalveolar carcinomacomponent is frequently associated with foci of high-grade atypical adenomatous hyperplasia. Am JClin Pathol. 2002;117:464-70.

94. Okubo K, Mark EJ, Flieder D, et al. Bronchoalveolar carcinoma: clinical, radiologic, and pathologicfactors and survival. J Thorac Cardiovasc Surg. 1999;118:702-9. Source URL: http://www.cancernetwork.com/lung-cancer/systemic-approaches-multifocal-bronchioloalveolar-carcinoma-there-appropriate-target

Links:[1] http://www.cancernetwork.com/review-article[2] http://www.cancernetwork.com/lung-cancer[3] http://www.cancernetwork.com/oncology-journal[4] http://www.cancernetwork.com/authors/benjamin-p-levy-md[5] http://www.cancernetwork.com/authors/alexander-drilon-md[6] http://www.cancernetwork.com/authors/liana-makarian-md[7] http://www.cancernetwork.com/authors/amit-patel-md

of 16

http://www.cancernetwork.com/lung-cancer/systemic-approaches-multifocal-bronchioloalveolar-carcinoma-there-appropriate-target

http://www.cancernetwork.com/lung-cancer/systemic-approaches-multifocal-bronchioloalveolar-carcinoma-there-appropriate-target


[8] http://www.cancernetwork.com/authors/michael-l-grossbard-md

of 16

systemic approaches for multifocal bronchioloalveolar ... filebronchioloalveolar carcinoma (bac) is...

Documents