Current Status of Adjuvant Chemotherapy for Stage IB Non–Small-Cell Lung Cancer: Implications for the New Intergroup Trial

mini-review

Current Status of Adjuvant Chemotherapy for Stage IB Non–Small-Cell Lung Cancer: Implications for the New Intergroup Trial Heather A. Wakelee,1 Joan H. Schiller,2 David R. Gandara3 Clinical Lung Cancer, Vol. 8, No. 1, 18-21, 2006 Key words: Carboplatin, Cisplatin, Early stage, Postoperative chemotherapy

Abstract

Background

Adjuvant chemotherapy after resection of stage II-IIIA non–small-cell lung cancer is now the standard of care based on the results of 3 phase III studies using cisplatin-based regimens, IALT (International Adjuvant Lung Trial), The National Cancer Institute of Canada JBR.10, and ANITA (Adjuvant Navelbine International Trialist Association). The role of adjuvant chemotherapy for stage IB disease remains controversial, even more so now that the updated results from CALGB (Cancer and Leukemia Group B) trial 9633 are statistically negative. CALGB 9633 was the only randomized adjuvant trial to use a carboplatin backbone and focused exclusively on patients with stage IB disease. Initial results, reported in 2004, showed a significant survival advantage with the addition of chemotherapy, but the 2006 updated results are no longer statistically significant. The next large intergroup adjuvant trial in non–smallcell lung cancer will look at bevacizumab in combination with chemotherapy. Because of the recent update, this trial will now limit patients with stage IB disease to those with larger tumors (* 4 cm) and will likely include only cisplatin-based regimens.

Recommendations for adjuvant chemotherapy for resected early-stage non–small-cell lung cancer (NSCLC) have changed completely in the past few years and continue to evolve. Before 2003, no large randomized studies had conclusively demonstrated the benefit of adjuvant chemotherapy after resection of NSCLC, despite the results of a 1995 metaanalysis demonstrating a nonsignificant 5% survival advantage at

1Stanford

Cancer Center, CA 2Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas 3University of California Davis Cancer Center, Sacramento Address for correspondence: Heather Wakelee, MD, Stanford Cancer Center, 875 Blake Wilbur Dr, Room 2233, Stanford, CA 94305-5826 Fax: 650-724-3697; e-mail: [email protected]

5 years with the addition of cisplatinbased chemotherapy.1 Notably, several phase III studies performed after the metaanalysis including ECOG 3590 (Eastern Cooperative Oncology Group; Intergroup Trial 0115), the BLT (Big Lung Trial), and the ALPI (Adjuvant Lung Project Italy), also failed to show a significant benefit with adjuvant chemotherapy (Table 1).2-12 Then in 2003, the positive results of the IALT (International Adjuvant Lung Trial)

Table 1: Recent Phase III Studies and Metaanalyses of Adjuvant Chemotherapy for Early-Stage NSCLC2-12 Trial

Stage

Number of Patients

ECOG 35902

Chemotherapy Regimen

Hazard Ratio

P Value

II-IIIA

488

Cisplatin/VP16

0.93*

0.56

BLT3

I-III

381

Cisplatin/4 options

1.02

0.9

ALPI4

I-III

1209

Cisplatin/MVd

0.96

0.585

I-III

1867

Cisplatin/Vinca Alkaloid or VP16

0.86

< 0.03

NCIC JBR.106

IB-IIB

482

Cisplatin/Vinorelbine

0.7

0.012

CALGB 9633 (2004)7

IB

344

Carboplatin/Paclitaxel

0.62

0.028

IB-IIIA

840

Cisplatin/Vinorelbine

0.79

0.013

CALGB 9633 (2006)9

IB

344

Carboplatin/Paclitaxel

0.8

0.1

UFT11

I

978

Uracil-Tegafur

0.71

0.04

95% Stage I

2003

Uracil-Tegafur

0.74

0.001

I-III

4584

Platinum doublets

0.89

0.0004

IALT5

ANITA8

UFT

12†

LACE10†

*Relative survival likelihood. †Metaanalyses. Abbreviations: LACE = Lung Adjuvant Cisplatin Evaluation; NCIC = National Cancer Institute of Canada; MVd = mitomycin C/vindesine; VP16 = etoposide

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Clinical Lung Cancer July 2006

resected stage II-IIIA NSCLC. The initial positive results of CALGB 9633 kept the role of adjuvant chemotherapy for stage IB open, despite the negative results from the subset analyses of the other 3 trials. An update of CALGB 9633, presented at the 2006 Annual Meeting of the American Society of Clinical Oncology, has further clouded the issue of adjuvant chemotherapy in stage IB disease. At the initial 2004 presentation of CALGB 9633, only 88 deaths (57% of the 155 required for final analysis) had occurred, with an HR for overall survival (OS) of 0.62 (P = 0.028). The update this year is based on 137 events, now with an HR for OS of 0.8 (P = 0.1).9 A statistically significant survival advantage is still observed at 2 and 3 years, but statistical significance is lost by 5 years, wide confidence intervals (CIs) notwithstanding. Failure-free survival still favors the chemotherapy arm (HR, 0.74; P = 0.03). It is unlikely that survival significance will be regained with the additional 18 events (12%) that are awaited, but the total accrual was only 344 patients, much fewer than originally planned. The initial accrual target was 500 patients, which was reduced to 384 patients in 2000 because of slow accrual and further reduced with early closure of the trial because of the initial positive results at interim analysis. It must be noted that for an HR of 0.8 to be statistically significant, the trial would have required > 1000 patients. There are many possible explanations for the negative results now reported with CALGB 9633, including an underpowered study, a true lack of benefit from adjuvant therapy in patients with stage IB disease, or a true lack of benefit from carboplatin- (as opposed to cisplatin-) based adjuvant chemotherapy (Table 1). A recent individual patient metaanalysis of the large adjuvant trials conducted since the 1995 metaanalysis (excluding CALGB 9633) by Pignon et al helps to put these findings into perspective.10 This study found a 5.5% survival advantage at 5 years (HR, 0.84; P < 0.001) for adjuvant cisplatin therapy overall, thus reinforcing the need to power adjuvant trials for this range of benefit. Their stage IB subset

analysis trended toward benefit (HR, 0.92) but failed to reach statistical significance (95% CI, 0.73-0.95), whereas a detriment for chemotherapy was suggested in stage IA. This metaanalysis provides further support for the position that the benefit of platinum agent–based adjuvant chemotherapy, if it exists, in stage IB is small and would require a prohibitively large trial to be detected. Perhaps looking at patients at higher risk as opposed to the entire stage IB population is the proper strategy. To support this position, in an unplanned subset analysis, patients on CALGB 9633 with tumors * 4 cm (approximately 100 patients on each arm) did have an OS advantage, with an HR of 0.66 (P = 0.04).9 The 74 patients on each arm with tumors < 4 cm did not differ in survival based on treatment, with an HR of 1.02 (P = 0.51; Table 1). Whereas the studies cited earlier all consisted of platinum agent–based therapy, the largest trials in stage I NSCLC adjuvant therapy have been conducted in Japan with the oral agent uracil-tegafur (UFT), administered daily for 2 years. A randomized phase III study of 978 patients with stage I adenocarcinoma was reported in 2003, demonstrating an HR for survival of 0.71 (P = 0.04; Table 1).11 The HR for UFT in a metaanalysis of 6 trials (95% CI, stage I) is 0.74 (P = 0.001) in an analysis of just > 2000 patients.12 The benefit was limited to those with a tumor size of * 2 cm. These studies are now the only trials showing a positive survival benefit with adjuvant chemotherapy in stage IB NSCLC. However, UFT, a drug not available in North America, was used in a very different manner as prolonged daily maintenance. Where should we go from here in the study of adjuvant therapy for NSCLC? Eastern Cooperative Oncology Group trial 4599 evaluated carboplatin/ paclitaxel with or without bevacizumab, an antivascular endothelial growth factor antibody, and found a median survival of 10.2 months versus 12.5 months (P = 0.007), favoring the bevacizumabcontaining regimen in patients with advanced-stage NSCLC.13 These results make the addition of bevacizumab to

Clinical Lung Cancer July 2006

mini-review research in brief

were reported. A statistically significant 4% survival advantage at 5 years (hazard ratio [HR], 0.86) with the addition of 4 cycles of cisplatin-based chemotherapy after complete resection of stage I-III NSCLC was demonstrated, mirroring the results of the 1995 metaanalysis (Table 1).5 This trial included 1867 patients, roughly equally divided between stages I-III, who were randomized to receive cisplatin-based chemotherapy versus observation. The study was not stratified to evaluate results by stage, but a trend toward increased benefit in patients with stage II/III disease was identified. In 2004, 2 additional positive adjuvant trials were reported. The National Cancer Institute of Canada JBR.10 trial randomized 482 patients with completely resected stage IB-IIB NSCLC to receive 4 cycles of cisplatin/vinorelbine versus observation.6 A 15% survival advantage was reported at 5 years (HR, 0.7) with the addition of chemotherapy (Table 1). The trial was stratified by stage, and, in subset analysis, no benefit was noted for patients with stage IB disease. However, in the same year, the CALGB (Cancer and Leukemia Group B) trial 9633 of 344 patients with resected stage IB NSCLC did report a survival advantage for those receiving adjuvant carboplatin/paclitaxel chemotherapy versus observation.7 This was the only adjuvant trial to use a carboplatin-based regimen. CALGB 9633 was closed early when the first interim analysis demonstrated a 12% survival advantage at 4 years (HR, 0.62). Confirmation of the overall beneficial role of adjuvant therapy was demonstrated in 2005 with the results of the ANITA (Adjuvant Navelbine International Trialist Association) trial. This study of 840 patients with resected NSCLC, nearly equally balanced between stages IB/IIIA, found a 9% survival advantage at 5 years (HR, 0.79) with 4 cycles of adjuvant cisplatin/vinorelbine (Table 1).8 Again, however, no benefit was found for the patients with stage IB disease on subset analysis. With the results of these positive trials, adjuvant chemotherapy was established as the standard of care for completely

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research in brief

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Figure 1: E1505 Adjuvant Chemotherapy with or Without Bevacizumab in NSCLC Eligible: Resected stage IB-IIIA * Lobectomy No previous CT No planned XRT No history of CVA/TIA No ATE within 1 year

Stratified: - Stage (IB [* 4 cm], II, IIIA-N2, IIIA-T3 N1) - Histology (squamous vs. other) - Sex - Chemotherapy regimen*

R A N D O M I Z E

Chemotherapy  4 cycles Chemotherapy  4 cycles plus Bevacizumab  1 year

*Investigator’s choice of 3 chemotherapy regimens. Abbreviations: ATE = arterial thromboembolic events; CT = chemotherapy; CVA = cerebrovascular accident; TIA = transient ischemic attack; XRT = external beam radiation therapy

adjuvant chemotherapy a compelling research question. Eastern Cooperative Oncology Group trial 1505 (E1505) is the proposed North American Intergroup trial to investigate the addition of bevacizumab to adjuvant chemotherapy. This study has an 85% power to detect an HR of 0.79 (26.5% OS advantage) with the addition of bevacizumab. Initially, the study was designed to include patients with stage IB-IIIA resected NSCLC, stratified by stage, histology, sex, and chemotherapy regimen, and also to give investigators the choice 1 of 4 chemotherapy regimens before randomization (Figure 1). Because of the updated CALGB 9633 data, the inclusion of patients with stage IB disease in E1505 is now being reconsidered. Exclusion of all patients with stage IB disease was one alternative, but would have essentially closed the last major opportunity to address the role of adjuvant platinum agent–based therapy in this patient population. Because of the positive trends seen in CALGB 9633 and the Pignon et al metaanalysis, as well as the positive results from Japan with UFT, exclusion of all patients with stage IB disease might not be the proper approach. Instead, limiting the study to patients with higher-risk stage IB disease (ie, patients with larger tumors) might be more appropriate. For this reason, the trial is now being modified to include only patients with stage IB disease with tumors * 4 cm. E1505 will include extensive correlatives that could help us better identify the patients who will benefit from adjuvant therapy. The adjuvant trials to date have used several chemotherapy regimens.

Clinical Lung Cancer July 2006

IALT used cisplatin with etoposide or a vinca alkaloid. JBR.10 and ANITA used cisplatin/vinorelbine. Carboplatin/ paclitaxel was the regimen used in the CALBG 9633 trial. The options in E1505 initially were to include carboplatin/ paclitaxel, cisplatin/vinorelbine, cisplatin/ docetaxel (superior to cisplatin/vinorelbine in 2 large randomized phase III trials for advanced-stage NSCLC),14,15 or cisplatin/gemcitabine (different toxicity profile, proven efficacy equivalent to other platinum doublets in advanced-stage disease [ECOG 1594],16 and an ongoing European trial examining this regimen with bevacizumab has not disclosed any unexpected toxicity reported to date). Just as the updated results from CALGB 9633 bring up the question of whether to include stage IB in E1505, they also bring up the question of whether to include a carboplatin-based regimen. CALGB 9633 was the only adjuvant trial to use carboplatin but was also the only trial to evaluate only patients with stage IB disease, a subset with no benefit in other adjuvant trials. For guidance, we must turn to data from advanced-stage disease to get a better sense of whether carboplatin and cisplatin are likely to be equivalent in the adjuvant setting. The CISCA (cisplatin vs. carboplatin) metaanalysis presented at the American Society of Clinical Oncology 2006 meeting, based on individual patient data from 2968 patients in 9 trials that compared a cisplatin- with a carboplatinbased regimen in advanced-stage disease, is of value in making this assessment.17 This study differed from the earlier Hotta et al and Zojwalla et al metaanalyses, which were based on published information and

showed a slight superiority of cisplatin.18,19 In the CISCA analysis, response rates were 33% with cisplatin versus 26% with carboplatin, which correlated to an HR of 1.37 (P < 0.001). The HR for survival, however, was 1.07 (P = 0.1). Only subset analyses that consisted of third generation drugs or nonsquamous histology were statistically better for the cisplatin regimens. Therefore, although a trend toward better survival in advancedstage disease with cisplatin-based regimens could translate into a significant survival advantage in the adjuvant setting, this remains only conjecture. The inclusion of carboplatin in E1505 remains under discussion but will likely not remain in the final protocol.

Conclusion We have reached a new era of adjuvant therapy for NSCLC, but continued progress must be made. Bevacizumab is the only targeted therapeutic agent ever shown to prolong survival when added to first-line chemotherapy for advanced-stage NSCLC. As such, bringing bevacizumab into the therapy of early-stage NSCLC is clearly the next logical research question in adjuvant therapy for NSCLC. E1505 is anticipated to open for accrual in fall 2006, and will be available through the Lung Intergroup and the National Cancer Institute’s Cancer Trial Support Unit. Participation in this high-priority study is encouraged.

References

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