Emerging Approaches to Advanced Bronchioloalveolar Carcinoma Howard West, MD Address Swedish Cancer Institute, 1221 Madison Street, Second Floor, Seattle, WA 98104, USA. E-mail: [email protected] Current Treatment Options in Oncology 2006, 7:69–76 Current Science Inc. ISSN 1527–2729 Copyright © 2006 by Current Science Inc.

Opinion statement Bronchioloalveolar carcinoma (BAC) is a subtype of non–small cell lung adenocarcinoma that has distinct epidemiologic, histologic, radiographic, and clinical features. The strict pathologic definition requires an absence of any invasion through the basement membrane into pulmonary parenchyma, but there is a growing consensus based on recent clinical studies that this diagnosis should be considered to be based on the clinical features of diffuse ground-glass opacities with minimal or no extra-thoracic spread and histology demonstrating adenocarcinoma with a lepidic growth pattern characteristic of BAC, even if there is a component of invasive adenocarcinoma. Although unifocal or even potentially oligometastatic disease is appropriately treated with resection, advanced BAC is generally treated with systemic therapy. However, multifocal BAC may be indolent enough to follow asymptomatic patients without any systemic therapy if patients are comfortable with this approach, because the rate of disease progression may be slow enough to warrant no therapy for many months or even years. For patients who have symptoms and/or clear evidence of progression over a short interval, standard chemotherapy is appropriate, but I would consider treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib to be the most appropriate initial therapy. This is based on the well-documented activity of the EGFR TKIs erlotinib and gefitinib, the latter no longer commercially available in advanced BAC. Advanced BAC is now emerging as an area of significant research, and clinical trials are particularly appealing considerations for such patients.

Introduction Bronchioloalveolar carcinoma (BAC) is a subtype of non– small cell lung cancer (NSCLC) for which controversy exists regarding pathologic definition, staging, response evaluation, and optimal treatments for resectable and diffuse, unresectable disease. The modern definition of this entity and the diagnosis of “bronchioloalveolar carcinoma” was by Liebow [1] in 1960, who provided the following description: “Generally well-differentiated adenocarcinomas primarily in the periphery of the lung beyond a grossly recognizable bronchus, with a tendency to spread chiefly within the confines of the lung by aerogenous and lymphatic routes, the walls of the distal air spaces often acting as supporting stroma for the neoplastic cells.” However, as discussed in detail in the following text, the pathologic criteria for BAC remain in evolution.

Bronchioloalveolar carcinoma has previously been considered to be unusual, but several recent reports indicate that it is steadily increasing in incidence [2,3]. Among histologic subtypes of NSCLC, BAC has unique clinical presentation, radiologic features, natural history, and response to systemic therapies. This paper reviews each of these aspects of BAC.

DEMOGRAPHICS AND ETIOLOGY The demographics of patients with BAC are also significantly distinct from those of patients with NSCLC. Although women represent less than 40% of NSCLC patients in general [4], women comprise more than 50% of the cases of BAC [4,5•,6,7]. In addition, whereas nonsmokers make up generally only approximately

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Table 1. Percent of BAC patients with symptoms at presentation (n = 134) Symptom Asymptomatic Cough Sputum production Dyspnea Chest pain Fever Hemoptysis Fatigue Weight loss Other

Patients, % 68 22 17 4 10 3 4 3 4 4

BAC—bronchioloalveolar carcinoma. (Data from Daly et al. [18•].)

10% to 15% of overall NSCLC populations, lifelong nonsmokers may represent up to one third of BAC series. Comparisons of BAC to other lung cancer populations have demonstrated a significant overrepresentation of nonsmokers in the former [6–8]. A younger age distribution than typically seen in NSCLC has also been reported [5•,9] but has been less consistent [4]. Previously considered to be a rare subtype that accounted for 2% to 3% of NSCLC cases [10,11], recent series have demonstrated consistently higher incidence rates, in some cases up to 15% to 20% [2,3,8]. Some of the large variability is attributed to differences in the pathologic interpretation of what is defined as BAC at various institutions, as discussed in the following text. The underlying cause of BAC remains undefined. This clinical entity is strikingly similar to a disease known as jaagsiekte, or pulmonary adenomatosis in sheep [12]. This diffuse pulmonary disease appears to share the same histology and ultrastructural analysis as BAC in humans [12], and sheep with this disease also may develop frothy sputum [13]. This sheep lung cancer is caused by a beta retrovirus, Jaagsiekte sheep retrovirus, with spread between sheep [12]. In contrast, cases of spread from sheep to humans have been exceptionally rare [14,15]. Neither viral DNA nor RNA has been found in human BAC cases [16,17].

CLINICAL AND RADIOGRAPHIC PRESENTATION The presenting symptoms of BAC are shown in Table 1. Up to two thirds of patients are asymptomatic at the time of diagnosis, and cough is the most common presenting symptom, seen in approximately one quarter to one third of patients [9,18•]. Approximately 5% to 10% of patients with BAC experience high-volume bronchorrhea [19], the copious production of frothy sputum that may be up to several liters per day and may result in fluid and electrolyte abnormalities [20,21]. This symptom is generally associated with a worse prognosis [22].

Routine chest radiographs show discrete or diffuse areas of air-space consolidation that may extend throughout one or more pulmonary lobes and are often interpreted as pneumonia initially (Fig. 1A). On CT scans of the chest, BAC lesions typically appear as semisolid, ground-glass opacities, which may be isolated or potentially very multifocal and diffuse (Fig. 1B). Although rate of progression and metabolic activity may vary, BAC lesions often have too low of a cellular density and too low a cellular turnover to demonstrate clearly abnormally increased glucose uptake on positron emission tomography scans, frequently resulting in false-negative results [23,24]. A higher proportion of patients with BAC presents with earlier-stage, resectable disease rather than other forms of NSCLC [8]. Approximately 45% to 60% of patients present with stage I or II disease, with stage I cases predominating in light of the infrequency of nodal involvement. Most stage III presentations are attributed to T4 disease from multiple lesions within the same lobe. Very diffuse disease involving multiple lobes and bilateral disease may also be seen in some cases at initial presentation.

HISTOLOGIC DEFINITIONS OF BRONCHIOLOALVEOLAR CARCINOMA One of the primary controversies within the subject of BAC arises from the definition of the clinical entity. As noted earlier, estimates of the incidence of BAC vary widely, largely because of a range in the interpretation of what constitutes BAC histologically. The World Health Organization (WHO) defines the spectrum from this distinct entity to the more common invasive adenocarcinoma (Fig. 2) [25]: 1. BAC: adenocarcinoma variant that grows along pre-existing alveolar structures without evidence of stromal, vascular, or pleural invasion a) mucinous: mucous producing b) non-mucinous: with Clara cell differentiation 2. Adenocarcinoma with BAC features: adenocarcinoma with BAC and invasive components 3. Invasive adenocarcinoma: adenocarcinoma variant that invades stroma and elicits a fibroblastic response Several subtypes of BAC have been described, with distinct malignant cells of origin. A non-mucinous subtype represents 40% to 60% of cases and arises from the Clara cell. The mucinous subtype comprises approximately 25% to 45% of cases and arises from the type II pneumocyte. In addition, some cases (10% to 15%) are designated as a mixed or indeterminate subtype of undefined cellular origin. It is unclear at this time whether different BAC subtypes demonstrate a different natural history or response to therapy, and at the

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Figure 1. Chest radiograph (A) and CT appearance (B) of multifocal BAC. BAC—bronchioloalveolar carcinoma.

Figure 2. The spectrum from pure BAC to invasive adenocarcinoma. A, Pure BAC; B, BAC with focal invasion; C, adenocarcinoma with BAC features; D, invasive adenocarcinoma. BAC—bronchioloalveolar carcinoma.

present time therapeutic plans are not routinely delineated on the basis of BAC subtype. In practice, patients with a typical clinical presentation and radiologic appearance of BAC may have histologic findings that include a noninvasive BAC pattern with a variable amount of invasive adenocarcinoma. In light of the practical limitations of the WHO definition and the evidence that pure BAC and the spectrum of BAC with limited invasive adenocarcinoma share very similar clinical characteristics [5•] and response to therapy [26,27], institutional rather than strict WHO definitions of BAC have been used in recent US-based clinical trials targeting patients with BAC.

NATURAL HISTORY/PROGNOSIS The pattern of spread of BAC involves nodal and distant metastatic disease much less frequently than typical invasive adenocarcinoma [8,28,29]. Instead, BAC tends to follow a pattern of multifocal disease within the lung parenchyma after presumed aerogenous spread [29–32]. Nodal disease is generally not seen,

concordant with the absence of invasion of basal membrane on histology. Death is characteristically secondary to respiratory failure in the setting of diffuse pulmonary involvement or intercurrent pulmonary infection, rather than from distant spread of cancer to involve other organ sites. Although some discrepancies exist, most of the rather limited literature on the natural history of early-stage and more advanced, unresectable BAC suggests that it exhibits a more indolent pattern of progression than do other NSCLC subtypes. Breathnach et al. [33], from Massachusetts General Hospital, described their retrospective experience of 33 patients with resected stage I BAC in comparison with 105 stage I adenocarcinomas resected over the same period. They found a significantly higher 5-year survival of 83% for resected BAC, compared with 63% for other adenocarcinomas. Similarly, Noguchi et al. [34••] also reported a higher long-term survival rate among patients with the most well-differentiated BAC tumors, and a stepwise decrease in 5-year survival as tumors transition from predominantly BAC/well-differ-

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entiated histology to more invasive and less well-differentiated adenocarcinomas. Multifocal, advanced BAC that is not resectable has also been shown to have a more prolonged survival than other forms of NSCLC. The group from Massachusetts General Hospital reported that the overall survival for 29 patients with advanced BAC was significantly better than that of 117 contemporary patients with other subtypes of advanced

N S C L C ( m e d i a n s u r v i va l 1 5 . 2 vs 9 . 7 m o n t h s, P = 0.007) [29]. Recent phase II prospective trials of advanced BAC, in which patients received cytotoxic chemotherapy [35] or molecularly targeted therapy against the epidermal growth factor receptor (EGFR) axis [36], also demonstrate a median survival of approximately 1 year, exceeding the wellestablished median survival of 8 to 10 months typically seen in trials of metastatic NSCLC.

Treatment Management of advanced bronchioloalveolar carcinoma Surgery • In certain circumstances, resection of multifocal BAC lesions has been performed and demonstrated to be feasible, with promising long-term survival. Roberts et al. [37•] reviewed their single-institution experience of complete pulmonary resections for 14 patients with multifocal BAC among a total of 73 patients with resected BAC. Among these 14 patients, nine had unilateral tumor distribution, and five had bilateral distribution. Although one patient had innumerable foci of BAC in a single lobe, the remaining patients had two or three lesions. Four patients demonstrated some differences in histology between lesions, suggesting distinct stage I primary cancers. The 5-year survival after resection of multifocal BAC was 64% in this retrospective series, leading the authors to suggest that resection of multifocal BAC lesions without nodal involvement is feasible and associated with far superior survival than would be expected for metastatic NSCLC in general. • In light of the propensity for BAC to spread in a primarily if not exclusively intrathoracic pattern, lung transplants have been performed in 32 cases of multifocal BAC [38–44]. Most patients developed recurrences, generally intrathoracic in the donor lung, and in some cases this occurred as long as 48 months postsurgery. These results are difficult to interpret in light of the well-described indolent natural history of BAC. This approach is clearly not feasible for most patients who present with multifocal BAC.

Systemic therapy • Up until very recently, conclusions about systemic therapeutic outcomes among patients with advanced, diffuse BAC had generally been based on retrospective experiences with cytotoxic chemotherapy at a single institution with a very limited number of patients. From such limited subsets, it remains unclear whether BAC is less responsive to standard chemotherapy than are other forms of NSCLC, as is widely perceived, or if response rates are similar [45••]. Conclusions have also been limited by difficulty in measuring response of BAC lesions, which are often poorly circumscribed on CT scans that are generally used for response assessment [46,47••]. • The Southwest Oncology Group (SWOG) conducted the first prospectively designed therapeutic trial for patients with advanced BAC, S9714 [35]. This trial included 58 chemo-naïve patients with advanced-stage BAC who underwent treatment with a prolonged (96-hour) infusion of paclitaxel, 35 mg/m2 per day, repeated every 3 weeks. The response rate of 14%, median progression-free survival of 5 months, and median overall survival of 12 months were accompanied by significant toxicity that limited interest in future study of this approach, but the trial provides a critical benchmark for clinical outcomes in a multicenter trial of patients with advanced BAC. The

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overall survival of 13% at 3 years on this protocol suggests that although these patients tend to survive longer than patients with other forms of advanced NSCLC, long-term survival is quite poor. Similar poor results for paclitaxel administered every 3 weeks in a study of 19 patients by the European Organization for Research and Treatment of Cancer (EORTC trial 08956) demonstrated a response rate of 11% and 1-year survival of 35% [48]. Taken together with the retrospective studies, it appears that although conventional chemotherapy may arguably achieve results in BAC that are comparable to those seen in the wider NSCLC population, these results leave considerable room for improvement, and novel approaches are particularly welcome in this clinical arena. • In addition to the importance of this trial as the first prospective trial aimed at therapy for patients with advanced BAC, SWOG S9714 included a collection of BAC tumor tissue that has emerged as a source for further critical study of this clinical entity. Hirsch et al. [49•] found that BAC tumors from this trial demonstrated a high frequency of EGFR protein expression by immunohistochemistry. Retrospective clinical data also support the unique sensitivity of BAC tumors to EGFR tyrosine kinase inhibitors (TKIs). Whereas only 10% to 20% of patients achieve an objective response when treated with EGFR TKIs [50,51], retrospective review of these data, and single-institution experience at Memorial Sloan-Kettering Cancer Center (MSKCC) with gefitinib on an expanded access protocol [52], demonstrated a significantly higher response rate to gefitinib among patients with adenocarcinoma, and particularly BAC tumors, compared with other lung cancer subtypes. These data, with multiple anecdotal reports of rapid and profound clinical and radiographic responses of patients with advanced BAC to treatment with the EGFR TKIs gefitinib and erlotinib, led to two recent phase II trials of these agents in a population of patients with advanced BAC. • SWOG trial S0126, a multicenter trial of gefitinib 500 mg orally daily in advanced BAC, represents the largest prospective trial that has ever been conducted in advanced BAC [36]. This trial included two patient cohorts, one chemotherapy-naïve and another previously treated with conventional chemotherapy, and accrued 138 eligible patients. Among the subset of patients with measurable disease, response rates were 19% and 9% for chemo-naïve and chemo-pretreated patients, respectively, using standard Response Evaluation Criteria in Solid Tumors (RECIST), known to be problematic in assessing poorly defined BAC lesions [46,47••]. Disease control/ nonprogression rates approached 50% in both cohorts. Complete responses were also seen, and several patients continue without evidence of disease progression beyond 1 year on treatment. Although the overall survival of 12 to 13 months for both cohorts is not markedly different from prior series, several clinical variables were associated with markedly superior survival in this trial, including female sex, development of rash versus no rash, smoking status of never smoked versus former/current, and Zubrod performance status of 0/1 versus 2. Histologic breakdown of BAC tumors demonstrated that the subset of patients with non-mucinous BAC appears to have markedly superior survival on gefitinib, compared with historical data with conventional chemotherapy [35]. • Another multicenter phase II trial, led by MSKCC and Vanderbilt-Ingram Cancer Center, accrued 83 patients with advanced BAC and treated with the other widely studied EGFR TKI, erlotinib at 150 mg orally [26]. As in the SWOG trial, 25% of the patients had been previously treated with chemotherapy. Of the 78 evaluable patients, 24% exhibited a partial response, with a median duration of response of 12 months. They found a greater likelihood of response among lifelong nonsmokers than among former

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Lung Cancer smokers or current smokers, and no responses were seen among patients who failed to develop a rash on erlotinib. Responses were not restricted to patients with pure BAC and in fact were more commonly seen in tumors that demonstrated adenocarcinoma with BAC than in pure BAC. • Taken together, the data from these two prospective trials clarify the use of EGFR TKIs in the treatment of BAC, in the frontline or salvage setting, although it appears that there remain distinct subsets that will benefit more or less from these agents. In addition, both of these prospective trials incorporated tumor tissue collection into these protocols, providing opportunities to study molecular correlates in BAC that may refine future targeted therapy strategies.

Future directions • Whereas the first prospective trials in BAC have only recently been completed and reported, a range of trials for advanced BAC are now emerging. Although gefitinib and erlotinib have now been tested in prospective trials of patients with advanced BAC, the utility of cetuximab, the chimeric monoclonal antibody against EGFR, remains undefined. The Eastern Cooperative Oncology Group is initiating a phase II trial for patients with advanced BAC who will receive single-agent cetuximab. • Other novel agent approaches are also being studied in BAC. There is currently an industry-led phase II international trial with a target enrollment of 150 patients with advanced BAC who will receive single-agent bortezomib (PS341). This trial is based on encouraging responses seen in patients with BAC enrolled in phase I and II studies [53,54], and anecdotal reports of encouraging responses of such patients to bortezomib, including responses in patients who have demonstrated progression on EGFR TKIs [55]. • The SWOG has recently closed a small phase II trial of the autologous cancer vaccine CG8123 (formerly GVAX; Cell Genesys, South San Francisco, CA), modified with an adenoviral vector to secrete the immunomodulator GM-CSF, which has been shown to have activity in a small number of patients with BAC [56]. Because the tumor is autologous, tumor tissue is required in order to manufacture each patient’s vaccine, generally requiring a surgical procedure to obtain an adequate amount of tissue. SWOG trial 0310 enrolled 19 patients with advanced BAC to undergo harvesting of tumor tissue to generate an autologous vaccine that was then administered to these patients. It closed very recently because of funding difficulties. • The SWOG is currently developing two phase II clinical trials for the setting of advanced BAC. The first, for patients who have previously received EGFR TKI therapy, will administer single-agent pemetrexed, based on the anecdotal reports of its significant activity in this population and the recent finding that a subgroup of BAC tumors expresses high amounts of alpha folate receptor and cluster with mesotheliomas using genes from the folate pathway [57]. For the patients who have not received erlotinib, the SWOG is developing a trial that combines erlotinib and bevacizumab, the monoclonal antibody to vascular endothelial growth factor. The latter trial is predicated on the proven role of erlotinib in advanced BAC, the preclinical additive effects of these agents, and the recently established survival benefit for adding bevacizumab to first-line chemotherapy in advanced NSCLC [58]. It remains to be determined whether adding bevacizumab to the potential current optimal systemic therapy for BAC of erlotinib will lead to further improvements in clinical outcomes for these patients. • Importantly, all of these clinical trials in BAC are now routinely incorporating correlative science studies that should offer additional insight into the underlying biology of BAC and may also help refine the treatment options for this clinical entity.

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References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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