Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study

H. L. West1,*, J. J. Crowley2, R. B. Vance3, W. A. Franklin4, R. B. Livingston5, S. R. Dakhil6, J. K. Giguere7, S. E. Rivkin1, M. Kraut8, K. Chansky2 and D. R. Gandara9

1 Swedish Cancer Institute/Puget Sound Oncology Consortium, Seattle, WA; 2 Southwest Oncology Group Statistical Center, Seattle, WA; 3 University of Mississippi Medical Center, Jackson, MS; 4 University of Colorado, Denver, CO; 5 University of Washington/Seattle Cancer Care Alliance, Seattle, WA; 6 Wichita Community Clinical Oncology Program, Wichita, KS; 7 Greenville Community Clinical Oncology Program,Greenville, SC; 8 Providence Cancer Institute,Southfield, MI; 9 University of California, Davis, Sacramento, CA, USA

* Correspondence to: Dr H. L. West, MD, Swedish Cancer Institute/PSOC, 1221 Madison St., 2nd Floor, Seattle, WA 98 104, USA. Tel: +1-206-386-2424; Fax: +1-206-386-2746; Email: howard.west{at}swedish.org


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:: There are no published prospective trials of chemotherapy for advanced bronchioloalveolar carcinoma (BAC), a subtype of non-small-cell lung cancer for which there is no current standard therapy. This phase II study assesses the efficacy and toxicity of 96-h paclitaxel in chemotherapy-naive patients with advanced BAC.

Patients and methods:: Patients with histologically confirmed stage IIIB (with pleural effusion) or stage IV BAC were eligible. Treatment consisted of paclitaxel 35 mg/m2/24 h continuously infused over 96 h (days 1–4) every 21 days for up to six courses.

Results:: A total of 58 eligible patients were enrolled. The objective response rate was 14% (all partial responses, 9% confirmed); 40% of patients demonstrated stable disease. The median progression-free and overall survivals were 5 and 12 months, respectively. Grade 3 or greater toxicities included neutropenia/granulocytopenia (43%), febrile neutropenia (12%), infection (22%), and stomatitis/pharyngitis (10%); there were five treatment-related deaths.

Conclusions:: S9714 represents the first prospective multi-institutional cooperative group trial focusing on treatment outcomes in BAC. Studies targeting this population are feasible, and while first-line paclitaxel administered as a prolonged infusion is active in this setting, toxicities limits the utility of this regimen. S9714 serves as a historical control for BAC patients against which future therapeutic approaches can be compared.

Key words: bronchioloalveolar carcinoma, paclitaxel, prolonged infusion, non-small lung cancer


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Bronchioloalveolar carcinoma of the lung (BAC) is a histological subgroup of non-small-cell lung cancer (NSCLC) that is steadily increasing in incidence and represents 2%–5% of new NSCLC cases [1Go, 2Go]. Distinguishing BAC further from other types of NSCLC is a high percentage of women, a somewhat younger age distribution and a higher incidence in non-smokers [3Go, 4Go]. Compared with other histological subtypes, BAC has a distinct clinical presentation, radiological appearance and natural history [3Go, 4Go]. In addition, the pathological diagnosis of BAC remains controversial. Nodal involvement and distant metastatic disease occur much less commonly than in other forms of NSCLC. Instead, it generally follows a much more localized growth pattern and may be spread aerogenously [5Go, 6Go]. Even for the subset of patients with advanced BAC, death is most typically from respiratory failure secondary to diffuse pulmonary involvement or intercurrent pulmonary infection, rather than from disease spread to other organ sites.

While patients may be cured after resection of focal BAC, there is no optimal established therapy for multilobar or recurrent disease. Because of the relative infrequency of the disease in the past, series of patients with BAC have generally been restricted to retrospective reviews of single institution experience in limited numbers of patients. BAC patients are often excluded from NSCLC clinical trials, and it remains unclear whether chemotherapy achieves therapeutic results comparable to those seen in more common NSCLC subtypes.

Paclitaxel is among the chemotherapy agents most commonly utilized in the treatment of NSCLC and has documented activity as a single agent or in combination with other chemotherapeutic drugs. Preclinical studies demonstrate reduction in development of MDR and increased cell killing associated with prolonged exposure to paclitaxel. Indeed, in vitro studies of paclitaxel infusions over 96 h suggested increased efficacy compared with shorter infusion durations [7Go, 8Go], while clinical studies of prolonged-infusion paclitaxel demonstrate significant activity in NSCLC and other malignancies, including in patients refractory to other paclitaxel schedules [9Go, 10Go]. Finally, anecdotal cases reported by the Southwest Oncology Group (SWOG) investigators of responses to 96-h paclitaxel among patients with advanced BAC contributed to the genesis of this study.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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Eligibility criteria
All patients enrolled were required to have histologically proven, stage IIIB (by pleural effusion) or IV BAC. Pathologic eligibility was based on institutional assessment, so that a histological diagnosis consistent with BAC by the participating institution was sufficient, although pathology was subsequently reviewed centrally. Cytologic specimens were not accepted for histological diagnosis.

Patients with a SWOG performance status of 0, 1 or 2 were eligible. Pre-study evaluation included: history and physical examination; complete blood count with differential and platelets, serum chemistries of alkaline phosphatase and bilirubin; chest radiograph; CT of chest, liver and adrenal glands. All patients had measurable or evaluable disease and had received no prior non-surgical therapy (including chemotherapy, radiation or biologics) for NSCLC.

Additional recommended evaluation included the following: serum creatinine, aspartate aminotransferase (AST) or alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and albumin; bone scan and/or brain CT or MRI based on symptoms and physician judgment. Patients with a history of brain metastases were ineligible for the present study.

Pregnant or nursing women were ineligible, and women and men of reproductive potential were unable to participate unless they agreed to use an effective contraceptive method. Eligible patients had no other prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient was in complete remission, or any other cancer from which the patient was disease-free for at least 5 years.

All patients were informed of the investigational nature of this study and signed a written informed consent in accordance with the local institutional review board and federal guidelines.

Study design
The S9714 treatment protocol consisted of single-agent paclitaxel administered at 35 mg/m2/24 h as a continuous infusion on days 1–4 of a 21-day cycle (140 mg/m2 total per cycle). Patients were premedicated with dexamethasone 20 mg p.o. 12 and 6 h prior to chemotherapy, as well as diphenhydramine 50 mg i.v. and ranitidine 50 mg i.v. or cimetidine 300 mg i.v. 30 min prior to initiation of paclitaxel infusion. Up to six cycles of chemotherapy were administered. Delays in chemotherapy and dose modification were performed for hematologic toxicity (absolute neutrophil count (ANC) <1500 cells/mm3 or platelets <100 000 cells/mm3; febrile neutropenia). Prophylactic granulocyte colony-stimulating factor (G-CSF) was not utilized.

Patients underwent repeat history and physical examination prior to each cycle. Prior to a fourth cycle, patients underwent repeat imaging to assess response to therapy. Additional imaging studies were performed after six cycles of paclitaxel. Subsequently, follow-up was performed every 6 months or as new clinical findings dictated. Patients were removed from protocol treatment for disease progression, unacceptable toxicity as assessed by the investigator, development of intercurrent, non-cancer related illnesses that prevented continuation of treatment, delay of treatment for more than 3 weeks, or upon patient request for any reason.

Study evaluation and statistical methods
All toxicities were graded according to National Cancer Institute (NCI) Common Toxicity Criteria Version 2.0. Response assessments (complete or partial response, stable disease or progressive disease) were made, with the following criteria. Complete response was defined as complete resolution of all radiological evidence of disease, no new lesions and resolution of any disease-related symptoms and abnormal laboratory values related to cancer. Partial response was defined as a ≥50% reduction in the sum of products of perpendicular diameters of all measurable lesions, with no new lesions or cancer-related symptoms or laboratory abnormalities. Progressive disease was defined as a >50% increase in the sum of products of perpendicular diameters of all measurable lesions or 10 cm2 (whichever is smaller) or clear worsening of evaluable disease or new lesions. Stable disease was defined as not qualifying for any of the aforementioned response categories. Objective response was not required for completion of the study protocol because the primary end point was overall survival. All patients were followed until death.

The primary objective of the present study was to determine whether 96-h infusion of paclitaxel demonstrates promising activity in terms of increasing survival and response rate in patients with BAC. Based on limited background information from a prior series of patients with BAC, a prospective definition of encouraging results included a true median survival from registration of 9 months or greater; the regimen would be considered of no further interest if the true median survival was 6 months or less. A target population of 50 patients accrued at an estimated rate of 25 patients/year and followed for an additional 6 months would provide a power of 0.81 to detect a 3-month difference in median survival from an estimate of 9 months. Overall and progression-free survival were determined based on the method of Kaplan and Meier [11Go]. Confidence intervals for the median overall and progression-free survival were calculated according to the method of Brookmeyer and Crowley [12Go].


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
S9714 was activated in May 1997 and closed to patient accrual in March 2000. Of 60 patients registered, one was ineligible due to having received previous radiotherapy and another received no protocol treatment and was not analyzable for any end point. Characteristics of 58 patients analyzed are shown in Table 1. In the present study, the median age was 68.0, with a range from 35 to 83 years of age. Twenty patients (34%) were male and 38 (66%) were female. Performance status (PS) was 0–1 in 51 patients and was 2 in seven patients. Fifty-one (88%) had stage IV disease, while the remaining seven (12%) had stage IIIB NSCLC with a pleural effusion. Disease was evaluable and response determinable in 45 of 58 patients (78%).


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Table 1. Patient demographics

 
Although an institutional definition of BAC was accepted for enrollment, tumor tissue was mandated and pathology was reviewed centrally. Correlation of histological and molecular findings from these BAC tumors has been correlated with clinical end points [13Go].

Treatment delivery
Twenty-seven patients (47%) completed all six cycles of paclitaxel. Failure to complete planned therapy was due to the following reasons: nine (16%) patients had prohibitive toxicity, 17 (29%) had evidence of progression of disease prior to completion of six courses of chemotherapy, and five (9%) died during therapy.

Toxicity
Maximum toxicities of 96-h paclitaxel infusion are illustrated in Table 2. Thirty-eight patients (66%) experienced grade 3 or higher toxicity. The most frequent grade 3/4 toxicity was neutropenia/granulocytopenia, occurring in 25 patients (43%); among these, seven (12%) experienced febrile neutropenia, including a single fatality. Other fatal toxicities included three deaths due to infection and one due to multiple organ failure, possibly related to therapy. Other toxicities were weakness/fatigue/lethargy, reported in 32 patients (55%), but grade 3 or 4 in only four patients (7%). Sensory neuropathy was observed in eight patients (14%): six (10%) were grade 1, and two (3%) were grade 2. Thromboembolic events were observed in four patients (7%).


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Table 2. Grade 3–5 toxicities

 
Response
Best radiographic response was determined among the 58 patients who received paclitaxel (Table 3). Among these, five (9%) had a confirmed and three (5%) had an unconfirmed partial response (PR); no complete responses (CR) were observed. Twenty-three patients (40%) demonstrated stable disease (SD), while progressive disease (PD) was recorded in 15 patients (26%). Six patients (10%) died prior to repeat imaging, while another six (10%) did not have assessment that was adequate for determining response and are assumed to be non-responders.


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Table 3. Clinical efficacy

 
Time to progression and survival analysis
With a median follow-up of 46 months, the median progression-free survival was 5 months (95% CI 3–6 months) (Figure 1). Median overall survival, illustrated by the Kaplan–Meier plot in Figure 2, is 12 months (95% CI 9–19); the 3-year survival is 13%.



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Figure 1. Progression-free survival among eligible patients with advanced BAC (n=58) who received paclitaxel by 96-h continuous infusion.

 


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Figure 2. Overall survival among eligible patients with advanced BAC (n=58) who received paclitaxel by 96-h continuous infusion.

 
BAC sub-histology
BAC sub-histology was determined on a subset of cases with adequate tissue and was defined by the current World Health Organization definition [14Go]. Upon central pathology review, three cases were determined to be pure adenocarcinoma without BAC features, and none of these three survived beyond 3 months. Median survival for BAC non-mucinous subtype (n=13) was 9 months. The median survival times for the BAC mucinous subtype (n=16) and the adenocarcinomas with BAC (n=5) were considerably better (17 and 18 months, respectively). Although responses were seen only among patients with BAC mucinous subtype (n=3) and adenocarcinoma with BAC features (n=2), the numbers in this post hoc subset analysis are too small to suggest any clear histological subgroups among patients with BAC that demonstrate greater or lesser clinical benefit from the treatment approach of this trial.


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
No established standard therapy exists for unresectable or recurrent BAC at the present time. While there are early reports of greater chemoresistance in BAC compared with more common subtypes of NSCLC [15Go, 16Go], a lack of progress in the management of this disease is, in part, related to the inability of single institutions to prospectively study and report results of uniform treatment approaches among sufficient numbers of patients with advanced BAC. The limited incidence of BAC makes it an ideal candidate for study in the multi-institutional cooperative group setting. Without question, the recently observed increasing frequency of BAC and higher proportion of females, non-smokers and younger age distribution together make it a highly relevant clinical problem. The accrual of nearly 60 uniformly staged and evaluated patients to S9714 demonstrates the feasibility of studying BAC within the SWOG network.

Prolonged infusion paclitaxel was selected as the treatment regimen for this patient population, based on the activity of this agent in the larger NSCLC population [17Go], the potential increased efficacy of 96-h administration compared with alternate schedules [18Go], and limited anecdotal observations of benefit for this regimen among patients with advanced BAC. In the present trial, this schedule was associated with considerable toxicity, most notably grade 3/4 hematological toxicity and fatigue/lethargy, each occurring in roughly half of the treated patients. In addition, five deaths during the trial were felt to be likely or possibly treatment-related. Partial responses were seen in 14% of patients and confirmed in 9%. Median time to disease progression was 5 months, and the median overall survival was 12 months. While the latter figure exceeds the prospectively defined threshold for designating the regimen as being of further clinical interest, in our assessment the toxicities observed, particularly the five treatment-related deaths, dampen enthusiasm for further study of this regimen in BAC. The median survival of 12 months is consistent with the modestly improved survival of BAC compared with other NSCLC subtypes, controlling for stage [3Go, 4Go, 19Go]. Because this is the largest series of patients presented with advanced BAC, absolute values for survival have been very limited in their potential generalizability, making this trial particularly critical as a benchmark for future studies of advanced BAC.

The relatively disappointing results for prolonged-infusion paclitaxel are consistent with several clinical trials of this approach in a variety of solid tumor settings [20Go]. After an initial report of a response rate of 27% among taxane-resistant patients with breast cancer [18Go], subsequent trials found a suggestion of improvement in efficacy and have not supported any additional study of this strategy [10Go, 17Go, 21Go–23Go].

In the present study, the 3-year survival for patients with multifocal or recurrent BAC was 13%. This result, along with similar findings of invariably poor outcomes within less than 2 years in smaller case series of patients with multifocal BAC [3Go, 15Go, 24Go], suggests that the general view of BAC as an indolent disease applies primarily to patients who present with earlier stage disease. In contrast, patients presenting with advanced and/or recurrent disease have a median survival measured in months and should be considered accordingly for therapy. Particularly in light of the absence of an optimal standard therapy, clinical trials are an ideal treatment option for these patients.

In conclusion, the current study demonstrates that although 96-h paclitaxel is active in the treatment of previously untreated patients with advanced BAC, with a median overall survival of 12 months, the toxicity of this regimen is considerable in BAC patients. We have established that this clinical entity can be studied effectively in a multi-institutional setting, providing the opportunity to systematically treat considerably larger cohorts of patients with BAC. Although the trial administered a chemotherapeutic regimen not widely used in NSCLC, this trial is the first to establish benchmark response rate and efficacy data for this growing patient population. As such, it provides a starting point for ongoing and future trials for patients with unresectable BAC. The recently closed SWOG protocol (S0126) evaluates the epidermal growth factor receptor tyrosine kinase inhibitor ZD-1839 (Iressa or gefitinib) in both chemotherapy-naïve and pretreated patients with advanced BAC, with accrual of more than 140 patients over approximately 18 months [25Go]. Multi-institutional cooperative group studies represent an opportunity to define a standard of care for BAC that has not been available previously.


    Acknowledgements
 
This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA38926, CA32102, CA35431, CA67663, CA20319, CA14028, CA35090, CA58348, CA45807, CA12644, CA74647, CA46368, CA42777, CA63850, CA35119, CA35192, CA68183, CA58416, CA46136, CA63845, CA58658, CA16385, CA67575, CA35281, CA58882, CA76462, CA58415, CA22433.

Received for publication October 21, 2004. Revision received January 28, 2005. Accepted for publication February 8, 2005.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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