The "C" Word (no, not that one) (page 2)

Dear wasasister,

I'm so sorry to hear this news about your brother-in-law. If you are looking for current information about his diagnosis and treatment, I highly recommend that you and his wife sign up with www.WebMD.com and with www.medscape.com - both are amazing repositories of medical journals, medical conference summaries on whatever medical topic you can imagine. WebMD is designed for non-medical folks, while medscape is for physicians and nurses and other health professionals.

You asked why medical folks describe tumors and growths by comparing them to fruit. LOL It took me a while to get used to doing that - but basically, the vast majority of growths in the human body are more-or-less spherical, and rather than saying it was an 8 centimeter diameter spherical shape, which can be difficult to visualize for a non-medical person, most of us have become accustomed to using various fruit as a common frame of reference. I've seen hemorrhoids the size of grapes, for instance. (ow!) And blood clots the size of grapefruits. Again (ow!).

Here's the latest Continuing Education offering on non-small cell carcinoma of the lungs (summer 2004) from Medscape: http://www.medscape.com/viewprogram/3220_pnt You won't find this kind of information on WebMD - so if you need some help with deciphering the articles, please let me know.

Love, Scully

American Society of Clinical Oncology 2004 Annual Meeting
Management of Lung Cancer CME

Complete author affiliations and disclosures are at the end of this activity. The materials presented here were prepared by independent authors under the editorial supervision of Medscape, and do not represent a publication of the American Society of Clinical Oncology. These materials and the related activity are not sanctioned by the American Society of Clinical Oncology or the commercial supporter of the conference, and do not constitute an official part of that conference.

Release Date:June 30, 2004; Valid for credit through June 30, 2005
Target Audience
This activity is intended for oncologists and other healthcare professionals who treat patients with cancer.
Goal
The goal of this activity is to define "state-of-the-art" treatment protocols and clinical strategies for the prevention, diagnosis, and management of cancer; to enhance the care of individuals with cancer; and to support quality clinical practice of healthcare professionals involved in their care.
Overall Learning Objectives
Upon completion of this activity, participants will be able to:
Discuss the various treatment options for breast cancer.
Evaluate the latest findings in the prevention and treatment of gastrointestinal cancers.
Identify new treatment strategies for genitourinary cancers.
Detail standard and novel treatment approaches in gynecologic cancers.
Review treatment approaches for all stages of hematologic malignancies.
Describe the therapeutic options for non-small-cell lung cancer.
Learning Objectives for this CME Activity
Upon completion of this activity, participants will be able to:
Describe the latest attempts to improve outcomes in patients with treatment-naive advanced non-small-cell lung cancer (NSCLC).
Detail the newest data on the use of targeted therapies in the management of patients with advanced NSCLC.

Legal Disclaimer
The material presented here does not reflect the views of Medscape or the companies providing unrestricted educational grants. These materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers or continuing education participants should verify all information and data before treating patients or employing any therapies described in this educational activity.

Contents of This CME Activity

Management of Early-Stage and Locally Advanced Non-Small-Cell Lung Cancer
Thomas J. Lynch, MD
Advanced Non-Small-Cell Lung Cancer: Focus on Treatment-Naive Patients
Corey J. Langer, MD, FACP
Advanced Non-Small-Cell Lung Cancer: Focusing on the Therapeutic Horizon in 2004
Corey J. Langer, MD, FACP

Management of Early-Stage and Locally Advanced Non-Small-Cell Lung Cancer

Thomas J. Lynch, MD

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States, Western Europe, and Japan. Despite great efforts at improving outcomes, only 15% of patients diagnosed with lung cancer in 2004 will be alive in 5 years. A major reason for this poor outcome is that fewer than half of the patients who present with NSCLC are candidates for surgery. Furthermore, less than half of those who undergo surgery are cured of their disease with resection alone. At the 40th Annual Meeting of the American Society of Clinical Oncology (ASCO), 2 critical studies supporting the use of adjuvant cisplatin-based chemotherapy were presented. These trials provide additional support for the observation first made in the International Adjuvant Lung Cancer Trial (IALT) by LeChevalier [1] at ASCO 2003 that adjuvant platinum-based chemotherapy improves a patient's chance of cure. Optimal integration of chemotherapy and radiation was the theme of the Cancer and Leukemia Group B (CALGB) trial reported by Vokes and colleagues, [2] which questions the role of low-dose weekly carboplatin/paclitaxel given with radiotherapy in the treatment of locally advanced disease. Presentations at ASCO 2004 also highlighted the potential role that stereotactic radiosurgery might have for patients with newly diagnosed early-stage lung cancer.

Adjuvant Chemotherapy Comes of Age: CALGB and National Cancer Institute of Canada Studies Provide Strong Evidence of Benefit

In 1995, the BMJ meta-analysis suggested that adjuvant chemotherapy with cisplatin-based regimens might be able to achieve survival prolongation in patients with completely resected lung cancer. [3] The study suggested a 5% absolute benefit, which was clinically meaningful, but did not reach the standards of statistical rigor to be convincing or to change practice. Partly as a result of this meta-analysis, a number of appropriately powered studies were started to address this question in a more rigorous fashion. The first of these to be reported was the Adjuvant Lung Project Italy (ALPI) trial, [4] which showed no benefit to adjuvant treatment. At 5 years, the curves were slightly separated, showing a benefit of 3% to 4%, yet this degree of benefit was not statistically significant despite the large size of the study. The first large-scale study to support adjuvant therapy was the IALT study reported in 2003 and published in early 2004. [1] This study involved nearly 1900 participants (roughly twice the size of ALPI) and demonstrated a clear-cut survival benefit with the addition of adjuvant therapy, showing an absolute benefit of 4% at 5 years.

At ASCO 2004, we heard the results of the CALGB trial reported for the first time. [5] This study was designed in the mid-1990s to compare adjuvant carboplatin/paclitaxel with no adjuvant therapy for patients with completely resected stage IB NSCLC. This trial has the advantage of using 1 regimen for a very select group of patients. Furthermore, the regimen is commonly used and the toxicity profile is acceptable.

The results of CALGB 9633 are shown in Table 1. This study was well balanced for known prognostic factors between the treatment and control arms. Most notably, the delivery of chemotherapy was excellent in the treatment group -- nearly 85% of patients in the treatment group received 4 cycles or more of chemotherapy.

Table 1. Patient Characteristics and Results of CALGB 9633

	Observation	Carboplatin/Paclitaxel
N	171	173
Men	63%	65%
PS = 0	58%	55%
Squamous histology	39%	39%

4-year PFS	50%	61%*
3-year OS	69%	82%*
4-year OS	59%	71%*

*Significant vs observation; PS = performance status; PFS = progression-free survival; OS = overall survival

CALGB 9633 demonstrates a remarkable improvement in overall survival as compared with the no-treatment group. Toxicity in this group of patients was minimal, with only 36% of patients having grade 3/4 myelosuppression. There were no treatment-related deaths -- which is an important aspect of an adjuvant study. Dose delays were uncommon, attesting to the well-tolerated nature of the chemotherapy.

The magnitude of benefit of the use of adjuvant carboplatin/paclitaxel was substantially greater than one might have predicted on the basis of IALT and the meta-analysis. It may well be that the terrific results were due to a uniform patient population, a regimen that was well tolerated and nontoxic, and the fact that such a high fraction of patients were able to get all 4 cycles of therapy. Whether the inclusion in this trial of a large number of women might have accounted for the positive results was raised by Dr. Kathy Pfisters of MD Anderson Cancer Center during her discussion of the trial.

The National Cancer Institute of Canada (NCIC) BR10 study [6] is another important adjuvant trial that has come in the wake of the BMJ meta-analysis and that was reported at ASCO 2004. BR10 randomized 482 patients with completely resected stage IB and stage II NSCLC to either observation or to 4 cycles of cisplatin/vinorelbine. The cisplatin was given on days 1 and 8, which allowed for better dose intensity. Like the CALGB study, this regimen was well tolerated with little toxicity seen and no toxic deaths.

The results of BR10 are shown in Table 2. Again, the arms were well balanced for known prognostic factors. Like CALGB 9633, a high percentage of patients (65%) received 3 or 4 cycles of chemotherapy. Also like the CALGB trial, there was a high percentage of women in this study -- at least compared with the IALT and ALPI trials.

Table 2. Patient Characteristics and Results of National Cancer Institute of Canada BR10

	Observation	Cisplatin/Vinorelbine
N	239	243
Men	64%	66%
PS = 0	49%	49%
Adenocarcinoma histology	53%	54%
Stage IB	45%	46%

5-year RFS	48%	61% *
5-year OS	54%	54%*

*P <05; PS = performance status; RFS = relapse-free survival; OS = overall survival

CALGB 9633 and BR10 should alleviate any concerns that existed after IALT regarding the benefit of adjuvant therapy. The magnitude of benefit is in line with that seen in breast, colon, and rectal cancers. Presumably, the major reason for the improved cure rate seen with adjuvant therapy of lung cancer is the ability to eradicate micrometastatic tumor cells in distant locations.

So, in 2004, what is the optimal adjuvant regimen? Should it be cisplatin or carboplatin? A meta-analysis at ASCO 2004 looked at the question of cisplatin vs carboplatin in the metastatic setting and determined that cisplatin was associated with a 1-month prolongation of survival as compared with doublet therapy on the basis of carboplatin. [7] Given the results of this meta-analysis, the results of TAX 326, [8] which showed a superior outcome to cisplatin/docetaxel as compared with carboplatin/docetaxel, and the Rosell [9] study, which showed that cisplatin/paclitaxel had a superior survival as compared with carboplatin/paclitaxel, it is likely that cisplatin-based regimens are going to be slightly better than carboplatin regimens. It is reasonable to extrapolate the results seen in metastatic patients to the adjuvant setting. Yet much of this improved benefit will hinge on actually being able to deliver 4 cycles on time in this setting. If the toxicity of cisplatin-based therapy is higher than carboplatin-based therapy, and one is not able to deliver all 4 cycles or not do this on time, then the very slim marginal benefit will fade.

For standard-risk patients, cisplatin combined with docetaxel, gemcitabine, vinorelbine, or etoposide should be considered standard. In this category, I would include those patients who have excellent performance status and those who would likely tolerate 4 cycles of therapy delivered at full dose and "on time." For others, carboplatin regimens make sense, and treatment with carboplatin combined with docetaxel, gemcitabine, or paclitaxel is reasonable.

As we move forward, what can we expect for adjuvant therapy in the future? Clearly the move toward targeted treatment will have an impact here. Given our ability to select patients who respond to gefitinib and erlotinib on the basis of the status of epidermal growth factor receptor tyrosine kinase (EGFR TK) mutations, it is reasonable to begin trials of adjuvant treatments on the basis of knowledge of mutational status. [10] Of course, an unknown at this point is how mutational status affects chemotherapy response and how one should optimally sequence chemotherapy and the EGFR TK inhibitors. Finally, antiangiogenic treatments are gaining increasing prominence in trials for patients with metastatic disease. The Eastern Cooperative Oncology Group (ECOG) is comparing carboplatin/paclitaxel vs carboplatin/paclitaxel and bevacizumab for patients with stage IV NSCLC. If this trial is positive for survival, it will beg the question of the role of bevacizumab in the adjuvant setting.

Two Cycles of Induction Chemotherapy Fail to Improve Outcome for Patients With Locally Advanced NSCLC

Locally advanced NSCLC has been an area of slow but steady progress over the past 15 years. The pioneering study of Dillman from the CALGB [11] established a role for sequential chemotherapy used with radiation vs radiation alone for stage III NSCLC. Recently, studies from the United States [12] and Japan [13] have clarified the case favoring concurrent chemoradiotherapy vs sequential chemoradiation in this setting.

However, several questions remain. Which concurrent chemoradiotherapy option is superior? What is the role of induction chemotherapy before chemoradiation or consolidation chemotherapy after chemoradiation in the treatment of patients with stage III disease? How are novel agents added to the current algorithm?

At ASCO 2004, we learned the results of CALGB 39801. [2] This study was a randomized trial comparing weekly carboplatin/paclitaxel given with concurrent radiation to 66 Gy vs 2 cycles of systemic doses of carboplatin/paclitaxel followed by the same concurrent weekly regimen. This study was well conducted, and reached its accrual goal in a very timely manner. A total of 366 patients were randomized across both arms. The balance of known prognostic factors was excellent. A major distinction between this trial and prior CALGB studies is that patients were permitted to enter regardless of the amount of prior weight loss -- which may have resulted in a different patient population being treated.

The results of CALGB 39804 are shown in Table 3. As can be seen, the overall survival favored the group that received induction therapy, but this did not reach statistical significance. The toxicity of both arms was reasonable, with the predicted increase in myelosuppression seen in the induction arm.

Table 3. Patient Characteristics and Results of CALGB 39801

	Weekly CT/XRT	CT x 2 → Weekly CT/ XRT
N	182	184
Men	70%	63%
Age > 70	26%	25%
PS = 0	46%	44%
Weight loss < 5%	63%	76%
Stage IIIA	50%	52%

Response rate	65%	60%
Median survival	11.4 months	13.7 months
3-year survival	17%	25%

CT = chemotherapy; CT/XRT = concurrent chemotherapy and radiotherapy; PS = performance status

What can one conclude from this trial? How do we place these data in the context of our current knowledge? Table 4 lists the results of 3 other recent studies. The first are the results of Southwest Oncology Group (SWOG) 9504, recently published by Gandara and colleagues, [14] which was a phase 2 study of full-dose cisplatin/etoposide with concurrent radiotherapy followed by 3 cycles of consolidation docetaxel. The second are the results of the Locally Advanced Multimodality Protocol (LAMP) trial [15] presented at ASCO 3 years ago, which is a randomized phase 2 study of weekly carboplatin/paclitaxel/radiotherapy with either 2 cycles of induction, 2 cycles of consolidation, or simply sequential therapy. Finally, in the last 2 columns are the results of the Radiotherapy Oncology Group (RTOG) trial 9410 comparing sequential vs concurrent chemoradiotherapy. [12]

Table 4. Summary of Trials in Locally Advanced NSCLC

	SWOG 9504	LAMP Sequential	LAMP Induction	LAMP Consolidation	RTOG Sequential	RTOG Concurrent
Median survival	27 months	13 months	12.8 months	16.1 months	14.6 months	17.1 months
2-year survival	NR	31%	22%	31%	NR	NR
3-year survival	37%	NR	NR	NR	NR	NR

NR = not reported

Compared with the 3 trials listed above, CALGB 39801 is certainly not compelling with regard to the overall survival of either group. Although induction appears slightly superior to no induction, it does not appear better than the results of sequential therapy obtained by the RTOG.

There are 2 reasons that the results of this CALGB trial may be so discouraging, both of which revolve around patient selection. First, by not restricting entrance to those who have lost less than 5% of weight, one could argue that the results of both arms of this current trial will suffer. Furthermore, this trial was conducted at a time when many investigators may have felt some discomfort putting their "best patients" on a trial in which the only systemic therapy for half the patients was 6 weeks of low-dose carboplatin and paclitaxel.

The results of CALGB 39801 also raise an important question as to the value of low-dose weekly chemotherapy when combined with radiotherapy in locally advanced NSCLC. The best cooperative group phase 2 and 3 data (such as the SWOG and RTOG studies) have used full-dose chemotherapy with agents that do not require dose attenuation when combined with chemotherapy. Given that the rationale for combined modality therapy is to both improve local control and to achieve tumor cell kill of "rogue" cells that may be micrometastatic, it may well be that systemic doses of chemotherapy will be needed. Of course, this will have important implications, because not all patients will be able to tolerate systemic doses of concurrent therapy due to functional status and end-organ function.

Stereotactic Radiotherapy Offers Option for Early-Stage NSCLC

Surgery is the most important curative approach for patients with early-stage NSCLC. Cure rates for patients with stage I and stage II disease in the United States can often exceed 70% in well-selected series. However, for some patients, surgery is not an option due to pulmonary function, comorbid disease, or simple refusal of the invasive procedure. In lieu of surgery, these patients have received external beam radiotherapy with modest success. Recent efforts to increase the intensity of radiation in this setting have included the use of 3-dimensional planning-based approaches and the use of intensity-modulated radiation therapy. The use of these modalities has allowed for an increase in the dose delivered to the tumor while reducing the dose delivered to the normal tissues.

Stereotactic radiation is the ultimate example of targeted dose intensity. This technique has had wide application to tumors of the central nervous system and has extended the ability of radiation to benefit these patients. At ASCO 2004, Onishi and colleagues [16] presented their results with stereotactic radiation therapy in patients with localized NSCLC. This group used a novel design to deliver biologically equivalent doses of greater than 100 Gy with a few fractions of radiotherapy. Of note, many of the patients in this series had an excellent performance status. In 281 patients, the overall 3-year survival after this approach was 95% in patients who were able to get biologically effective doses of > 100 Gy as compared with 69% in patients who received < 100 Gy.

Thoracic stereotactic radiotherapy was very well tolerated in this patient population, with acceptable rates of pulmonary toxicity. Additional studies will need to be done to confirm the ultimate value of this modality. The role of chemotherapy in this setting is also unclear. We know that concurrent chemotherapy and radiation are superior for nonsurgical stage III disease, and that adjuvant chemotherapy is now the standard of care in stages I, II, and III disease. It is intriguing to consider how chemotherapy could be integrated with this approach. Along with the recently developed technique of thoracic radiofrequency ablation, stereotactic radiotherapy provides an additional option to be considered when approaching patients who have marginal pulmonary function and NSCLC.

References

Le Chevalier T for the IALT Investigators. Results of the randomized International Adjuvant Lung Cancer Trial (IALT): cisplatin-based chemotherapy (CT) vs. no CT in 1867 patients (pts) with resected non-small cell lung cancer (NSCLC). N Engl J Med. 2004;350:351-360. Abstract
Vokes E, Herndon J, Kelly M, et al. Induction chemotherapy followed by concomitant chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell lung cancer (NSCLC): Initial analysis of a randomized phase III trial. Proc Am Soc Clin Oncol. 2004;23:616. Abstract 7005.
Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ. 1995;311:899-909. Abstract
Scagliotti GV, Fossati R, Torri V, et al.; Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer-Lung Cancer Cooperative Group Investigators. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst. 2003;95:1453-1461. Abstract
Strauss G, Herndon J, Maddaus M, et al. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633. Proc Am Soc Clin Oncol. 2004;23(suppl):17. Abstract 7019.
Winton T, Livingston R, Johnson D, et al. A prospective randomized trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage IB and II non-small cell lung cancer (NSCLC) Intergroup JBR.10. Proc Am Soc Clin Oncol. 2004;23(suppl):17. Abstract 7018.
Zojwalla NJ, Raftopoulos H, Gralla RJ. Are cisplatin and carboplatin equivalent in the treatment of non-small cell lung carcinoma (NSCLC)? Results of a comprehensive review of randomized studies in over 2300 patients. Proc Am Soc Clin Oncol. 2004;23:630. Abstract 7068.
Fossella F, Pereira J, von Pawel J, et al. Randomized, multinational, phase III Study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small cell lung cancer: the TAX 326 Study Group. J Clin Oncol. 2003;21:3016-3024. Abstract
Rosell R, Gatzemeier U, Betticher DC, et al. Phase III randomized trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol. 2002;13:1539-1549. Abstract
Lynch TJ, Bell D, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139. Abstract
Dillman R, Seagren S, Propert K, et al. A randomized trial of induction chemotherapy plus high dose radiation vs. radiation alone in stage III NSCLC. N Engl J Med. 1990;323:940-945. Abstract
Curran WJ, Scott C, Langer R, et al. Phase III comparison of sequential vs. concurrent chemoradiation for PTS with unresected stage III non-small cell lung cancer (NSCLC): initial report of radiation therapy oncology group (RTOG) 9410. Proc Am Soc Clin Oncol. 2000;19:Abstract 1891.
Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 1999;17:2692-2699. Abstract
Gandara D, Chansky K, Albain K, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol. 2003;21:2004-2010. Abstract
Choy H, Curran W, Scott W, et al. Preliminary report of locally advanced multimodality protocol (LAMP): ACR 427: a randomized phase II study of three chemo-radiation regimens with paclitaxel, carboplatin, and thoracic radiation (TRT) for patients with locally advanced non small cell lung. Proc Am Soc Clin Oncol. 2002;21:291a. Abstract 1160.
Onishi H, Nagata Y, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I non-small cell lung carcinoma: clinical outcomes in 273 cases of a Japanese multi-institutional study. Proc Am Soc Clin Oncol. 2004;23:615. Abstract 7003.

Advanced Non-Small-Cell Lung Cancer: Focus on Treatment-Naive Patients

Corey J. Langer, MD, FACP

Chemotherapy Plus Targeted Therapies in Treatment-Naive Advanced NSCLC

To date, no trial comparing standard chemotherapy and a targeted agent with combination chemotherapy alone has shown a survival advantage in patients with treatment-naive non-small-cell lung cancer (NSCLC). More than a dozen efforts have been mounted over the last half decade, all to no avail. At this year's annual meeting of the American Society of Clinical Oncology (ASCO), 2 additional studies, each evaluating the role of erlotinib (OSI-774), a small-molecule epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), met similar fates. The monoclonal antibody cetuximab (C225) did not fare much better, indicating that further research into the use of these agents in treatment-naive patients is clearly warranted.

The TRIBUTE trial [1] featured a direct comparison of combination paclitaxel/carboplatin vs identical chemotherapy plus erlotinib at a fixed dose of 150 mg daily. A total of 1059 patients with a performance status of 0-1 and advanced NSCLC were enrolled. The majority (> 60%) had adenocarcinoma. As shown in Table 1, there was no significant difference in response rate, time to progression, or survival, although there was a significant increase in rash and diarrhea in the erlotinib arm.

Table 1. Paclitaxel/Carboplatin ± Erlotinib in Advanced NSCLC (TRIBUTE)

	Erlotinib	Placebo
Overall response (%)	21.5	19.3
TTP (months)	5.1	4.9
Median survival (months)	10.8	10.6

TTP = time to progression.

Of note, in the small subset of patients who never smoked, the addition of erlotinib did confer a survival advantage: a median of 22 months vs 11 months for those who received chemotherapy alone. Last year, a landmark analysis performed by Herbst and colleagues [2] in patients who continued to receive treatment more than 90 days out on the a randomized phase 3 trial of paclitaxel/carboplatin ± gefitinib (INTACT 2) showed a borderline survival advantage for individuals with adenocarcinoma who remained on the experimental treatment arm (17.1 months vs 13.6 months; P = .05), suggesting a possible benefit to maintenance therapy. A similar evaluation of the TRIBUTE study would be illuminating.

A very similar randomized, phase 3, placebo-controlled trial (TALENT) presented by Gatzemeier and colleagues [3] evaluated gemcitabine/cisplatin ± erlotinib. Eligibility was essentially identical to the TRIBUTE effort, though the accrual was somewhat higher (n = 1172, at 164 sites worldwide). In addition, in contrast to TRIBUTE, there were more men and more patients with stage IIIB disease. As with TRIBUTE, there was no obvious difference in outcome.

Table 2. Gemcitabine/Cisplatin ± Erlotinib in Advanced NSCLC (TALENT)

	Erlotinib	Placebo
TTP (months)	5.6	6.0
OS (months)	9.9	10.1
1-year OS (%)	41	42

TTP = time to progression; OS = overall survival.

As with TRIBUTE, individuals on the TALENT trial receiving erlotinib in combination with gemcitabine/cisplatin experienced significantly more grade 3-4 diarrhea (6% vs < 1%), and grade 3-4 skin rash (10% vs < 1%).

Clearly, in the treatment-naive setting, the empiric combination of newer targeted agents with systemic chemotherapy, in the absence of a clear-cut tissue target, or a restricted, targeted patient population, is likely to meet with failure. Multiple, similar studies have proven negative. We need a better understanding of the critical pathways targeted by these newer biologic agents. The recently identified "activation mutations" cited by Lynch and colleagues [4] may help us delineate a subgroup likely to benefit. But it is naive to believe that a single target or mutation is sufficient, particularly in complex "multi-hit" neoplasms like lung cancer.

In a trial sponsored by both Merck and Bristol-Myers Squibb, the distributors of cetuximab, Rosell and colleagues [5] mounted a randomized, phase 2 effort evaluating cisplatin and vinorelbine either alone or in combination with cetuximab. This trial employed an unbalanced randomization (2:1) favoring the cetuximab arm. Treatment stipulated chemotherapy-naive NSCLC, with evidence of EGFR expression. A total of 86 patients were enrolled; 92% had stage IV NSCLC, and median Karnofsky performance score was 90. An equal percentage (42%) had either adenocarcinoma or squamous cell histology.

Those treated on the cetuximab arm demonstrated more asthenia and fatigue and a higher incidence of infection and acneiform rash, although there was no significant difference in gastrointestinal toxicity or leukopenia. The overall response rate was higher in the cetuximab arm (31.7% vs 20% in the control arm), but this difference was not statistically significant; nor was time to progression (4.7 months vs 4.2 months) or median survival (8.3 vs 7.0 months). The prospect of mounting a phase 3 trial of current standard chemotherapy ± cetuximab is not well supported by these results.

Conventional Cytotoxic Approaches in Treatment-Naive, Late-Stage NSCLC

Kubota and colleagues [6] presented a 4-arm phase 3 trial, which, ultimately, looked very similar to ECOG 1594, [7,8] although the arms were not identical. From October 2000 through June 2002, 602 patients were randomized to either paclitaxel 200 mg/m 2 and carboplatin AUC 6 (TC); cisplatin 80 mg/m 2 day 1, gemcitabine 1 g/m 2 days 1 and 8 every 3 weeks (GP); cisplatin 80 mg/m 2 day 1, vinorelbine 25 mg/m 2 days 1 and 8 every 3 weeks (NP); or cisplatin 80mg/m 2 day 1 and irinotecan 60 mg/m 2 days 1, 8, and 15 every 4 weeks (IP, the reference arm). The updated results are summarized in the Table 3.

Table 3. Four-arm Study of Chemotherapy Regimens in Treatment-Naive Advanced NSCLC

	TC	GP	NP	IP
N	145	146	145	145
RR (%)	32.4	30.1	33.1	31.0
TTP (months)	4.5	4.0	4.1	4.7
MST (months)	12.3	14.8	11.4	14.2
1-year OS (%)	51	60	48	59

TC = paclitaxel 200 mg/m 2 and carboplatin AUC 6; GP = cisplatin 80 mg/m 2 day 1, gemcitabine 1 g/m 2 days 1 and 8 every 3 weeks; NP = cisplatin 80 mg/m 2 day 1, vinorelbine 25 mg/m 2 days 1 and 8 every 3 weeks; IP = cisplatin 80mg/m 2 day 1 and irinotecan 60 mg/m 2 days 1, 8, and 15 every 4 weeks; RR = response rate; TTP = time to progression; MST = median survival time; OS = overall survival.

Median survival time was best for the GP and IP arms, at 14.8 and 14.2 months respectively, with virtually identical 1-year survival rates of 59% and 60%, but the differences were not statistically significant. Moreover, the IP arm resulted in significantly more diarrhea compared with the other arms and relatively more nausea. The TC arm resulted in significantly more sensory neuropathy. Although the reference arm of irinotecan/cisplatin is not widely used outside in North America or Western Europe, it remains the standard approach in Japan and certainly constitutes a reasonable alternative elsewhere in the world.

In the absence of clear benefit for one regimen over another, other researchers have investigated the role of different schedules. In a randomized phase 2 trial, Belani and colleagues [9] assessed weekly paclitaxel in combination with either monthly carboplatin or weekly carboplatin. A third arm employed high-dose paclitaxel (150 mg/m 2 ) weekly x 6 in combination with weekly carboplatin followed by low-dose maintenance paclitaxel 100 mg/m 2 days 1, 8, and 15 for 3 out of 4 weeks, in combination with weekly carboplatin.

In this pilot trial, arm 1, employing monthly carboplatin and weekly paclitaxel, yielded the best therapeutic index, with a median survival of 49 weeks, a median time to progression of 30 weeks, a 1-year survival rate of 47% (P < .01 vs 31% for arm 2), and the least toxicity. At this year's ASCO meeting, Belani [10] reported on a larger, formal phase 3 trial comparing this regimen with standard paclitaxel 225 mg/m 2 every 3 weeks in combination with carboplatin AUC 6 every 3 weeks. After 4 cycles, those without progressive disease on either arm had the option of continuing maintenance paclitaxel alone. A total of 444 evaluable patients were enrolled; the results are summarized in Table 4.

Table 4. Carboplatin + Paclitaxel Weekly or Once Every 3 Weeks in Treatment-Naive Advanced NSCLC

	Weekly Paclitaxel	Every-3-Weeks Paclitaxel
N	223	221
Median age	65	65
Male	60%	65%
Stage IIIB disease	17%	17%
Febrile neutropenia	0.9%	3.3%
Neuropathy, grade 2/3	16.6%	24.3% (P = .0471)
Arthralgias	1.4%	6.1% (P = .017)
Overall response rate	20.3%	18.2%
TTP (weeks)	16.4	17.6
Median survival (months)	38.7	44.5 (P = .338)
1-year OS (%)	39.5	43

TTP = time to progression; OS = overall survival.

These results strongly suggest that weekly paclitaxel can help reduce the incidence of neuropathy and arthralgias compared with the more conventional every-3-weeks dosing; these concerns are critical in elderly individuals and in those with tenuous performance status. Unfortunately, the weekly approach, which has been touted as having an additional antiangiogenic or proapoptotic effect, offered no other therapeutic advantage over the conventional approach. Although both arms yielded results that appeared a bit better than historical controls, this might have been due to better patient selection or to maintenance therapy with weekly paclitaxel.

References

Herbst RS, Prager D, Hermann R, et al. TRIBUTE - A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:617. Abstract 7011.
Herbst RS, Giaccone G, Schiller J, et al. Subset analysis of INTACT results for gefitinib (ZD-1839) when combined with platinum-based chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2003;22:627. Abstract 2523.
Gatzemeier U, Pluzanska A, Szczesna A, et al. Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:617. Abstract 7010.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations of the epidermal growth factor receptor underlying the responsiveness of NSCLC to gefitinib. N Engl J Med. 2004;350:2129-2139. Abstract
Rosell R, Daniel C, Ramlau R, et al. Randomized phase II study of cetuximab in combination with cisplatin (C) and vinorelbine (V) vs. CV alone in the first-line treatment of patients (pts) with epidermal growth factor receptor (EGFR)-expressing advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:618. Abstract 7012.
Kubota K, Nishiwaki Y, Ohashi Y, et al. Four-Arm Cooperative Study (FACS) for advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:616. Abstract 7106.
Schiller JH, Harrington D, Belani CP, et al. A randomized phase III trial of four chemotherapy regimens in advanced NSCLC. Proc Am Soc Clin Oncol. 2000;19:Abstract 2.
Schiller JH. Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98. Abstract
Belani CP, Barstis J, Perry MC, et al. Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. J Clin Oncol. 2003;21:2933-2939. Abstract
Belani CP, Larocca RV, Rinaldi DA, et al. A multicenter, phase III randomized trial for stage IIIB/IV NSCLC of weekly paclitaxel and carboplatin vs. standard paclitaxel and carboplatin given every three weeks, followed by weekly paclitaxel. Proc Am Soc Clin Oncol. 2004;23:619. Abstract 7017.

Advanced Non-Small-Cell Lung Cancer: Focusing on the Therapeutic Horizon in 2004

Corey J. Langer, MD, FACP

Salvage Therapy: The Redemption of EGFR-TKI

Although epidermal growth factor receptor (EGFR) inhibition has not yet shown a benefit in the front-line setting in patients with advanced non-small-cell lung cancer (NSCLC), a critical, pace-setting phase 3 trial presented at the American Society of Clinical Oncology (ASCO) 2004 meeting has rejuvenated our enthusiasm. Shepherd and colleagues [1] mounted a phase 3, randomized, placebo-controlled trial of erlotinib (150 mg daily) vs best supportive care in the second-/third-line setting. Stratification was based on prior response status, the number of previous chemotherapy regimens (1 vs 2), and performance status (PS; 0-1 vs 2). This phase 3 effort was prompted by results of a phase 2 study demonstrating a response rate of 12.3%, a median survival time of 8.4 months, and a 1-year survival rate of 40% in the salvage setting, [2] results that looked as good as, if not better than, those observed for the EGFR tyrosine kinase inhibitor (TKI) gefitinib in an identical setting. [3,4]

A total of 731 patients were accrued to this effort, which was primarily conducted in Canada, Europe, North America, and Latin America. With expanded targeted accrual, the statistical goals were revised to discern an improvement in survival from 4 months (baseline) to 5.3 months on the experimental arm. Fifty percent of the patients had adenocarcinoma and 90% had prior platinum exposure; the majority received 2 prior regimens. Results are summarized in Table 1.

Table 1. Erlotinib vs Best Supportive Care in NSCLC in the Salvage Setting

	Erlotinib	BSC
Overall response rate	8.9%	< 1%
Time to progression (months)	2.2	1.8 (P = .001)
Median survival (months)	6.7	4.7 (P = .001)
1-year survival rate	31%	22%

BSC = best supportive care.

These results definitively underscore the therapeutic superiority of erlotinib vs best supportive care in the second-line and third-line settings, and vindicate the use of EGFR TKIs. Given their similar mechanism of action, there is little reason to believe erlotinib would offer a therapeutic advantage over gefitinib.

Mohamed and colleagues [5] evaluated patients who had received gefitinib on the expanded access program and showed that rash and performance status correlated with outcome. Of 178 patients treated in this setting, PS 0-1 patients had a median survival of 5.8 months, compared with only 2.9 months for PS-2 patients (P < .0001). Similarly, patients with skin rash of any grade had a median survival of 11 months compared with 4.5 months for those without a rash (P < .0001), although it should be noted that many patients without rash simply did not receive treatment long enough to develop it, thus calling into question proposals for "dose to rash" studies.

Molecular and Clinical Prognostic Factors for EGFR-TKIs

A much awaited analysis of INTACT 1 and INTACT 2, two separate double-blind, placebo-controlled, randomized, multicenter trials, [6,7] evaluated tumor biopsies from 516 cases taken between diagnosis and the start of treatment. [8] Study design in each trial was similar to the TRIBUTE and TALENT efforts: chemotherapy du jour ± gefitinib in combination. The growth pattern and percent membrane staining proved predictive of survival, with improvement seen in patients who had both (P = .0011). In a multivariate analysis, the predictive capacity of this combination of findings held up, and proved independent of performance status; stage; bone, brain, or liver involvement; gender; histology; or weight loss.

Lynch and colleagues [9] recently identified the activation mutation in 8 of 9 gefitinib-responsive lung cancer patients, compared with 0 of 7 with no response (P < .001). This observation was made retrospectively in the context of compassionate release evaluation of this agent. These mutations proved to be either small frame deletions or amino acid substitutions clustered around the adenosine triphosphate-binding pockets of the tyrosine kinase domain. Identical mutations were observed in multiple patients, suggesting a "specific" gain of function, facilitating the activity of these agents in EGFR-positive patients, but this mutation does not explain the putative clinical benefit in patients with stable disease.

Perez-Soler, [10] in another analysis, demonstrated that resistance to erlotinib was associated with enhanced baseline expression of pERK 1/2, pAKT, and pSTAT-3 in many, if not all, cell lines. In addition, EGF-independent activation of downstream elements of the EGFR pathway were thought to be a common mechanism of clinical resistance to this agent.

Defining the Optimal Regimen in the Second- and Third-Line Settings

Based on the data to date, EGFR-TKI inhibitors are now considered the standard of comparison in the third-line setting. In addition, in the second-line setting, we have phase 3 data showing therapeutic benefit for docetaxel vs best supportive care, [11] and de facto therapeutic equivalence between docetaxel and pemetrexed. [12] Consequently, either docetaxel or pemetrexed can be considered the standards of comparison in the second-line setting.

Pujol and colleagues, [13] in a retrospective analysis of the recent randomized phase 3 trial comparing pemetrexed with docetaxel in the second-line setting, specifically evaluated the role of third-line treatment. Of 541 patients enrolled on the trial, 48% on the pemetrexed arm and 39% on the docetaxel arm went on to third-line treatment. In the pemetrexed arm, the median survival of patients who received docetaxel as third-line therapy was 9.6 months; for those receiving other chemotherapy as third-line therapy, the median survival was 10.6 months. These results strongly suggest that the putative survival benefit of pemetrexed was not due to later crossover to docetaxel. In another retrospective analysis from the same phase 3 trial, De Marinis and colleagues [14] evaluated symptom palliation using the lung cancer symptom scale. With the exception of hemoptysis, which did not improve for patients on the docetaxel arm, each agent resulted in similar benefit, with reductions seen in anorexia, fatigue, cough, dyspnea, and pain. Of note, patients with both objective response and stable disease derived subjective benefit.

In a separate phase 3 randomized trial of single-agent docetaxel 75 mg/m 2 every 3 weeks vs weekly therapy (35 mg/m 2 days 1, 8, and 15 every 4 weeks), 216 patients were enrolled between April 2000 and September 2003. [15] A total of 23.5% had previously been exposed to paclitaxel. The weekly regimen resulted in significantly less neutropenia (P < .0001) and alopecia. There was no significant difference in response rate: 9.7% for the conventional schedule; 7.6% for the weekly schedule. In general, severe toxicity was a bit less common for patients receiving the weekly approach.

The addition of second agents in the salvage setting, however, has not proven beneficial. Takeda and colleagues [16] mounted a randomized phase 2 trial evaluating single-agent docetaxel 60 mg/m 2 day 1 vs the combination of docetaxel 60 mg/m 2 day 8 and gemcitabine 800 mg/m 2 days 1 and 8 every 3 weeks (DG). A total of 142 patients were accrued from January 2002 through April 2003. The trial was aborted early after an unexpectedly high incidence of interstitial lung disease (ILD); 3 treatment-related deaths (5%) due to ILD occurred on the DG arm. There was no significant difference in the incidence of neutropenia, nausea, anorexia, constipation, or febrile neutropenia. However, there was significant increase in the incidence of dyspnea (23% vs 14%) and ILD (21% vs 2%) in the DG arm. Survival favored the DG arm (11.2 vs 10.1 months), as did 1-year survival rate (47% vs 38%); similarly, progression-free survival (PFS) was 3.1 months for those receiving DG vs 2.1 months for patients receiving single-agent docetaxel. However, in each of these comparisons, the hazard ratio crossed 1.

In another trial, a comparison between single-agent docetaxel and combination docetaxel plus irinotecan failed to elucidate a benefit for doublet therapy. [17] A total of 130 PS 0-2 patients with recurrent, platinum-exposed NSCLC were enrolled. Patients received docetaxel 75 mg/m 2 every 3 weeks or docetaxel 30 mg/m 2 days 1 and 8 in combination with irinotecan 60 mg/m 2 days 1 and 8 every 3 weeks. The overall response rate was higher in the combination arm (20% vs 14%), and time to progression showed a borderline significant trend toward improvement (5.6 vs 4.8 months; P = .065); however, there was no difference in the overall survival (6.5 vs 6.4 months) or 1-year survival rates (37% vs 34%). Moreover, grade 3 and 4 thrombocytopenia was more common in the combination arm (17% vs 6%; P = .04), and grade 3/4 anemia trended worse in the combination arm (23% vs 12%; P = .09).

Special Populations: Neglected Subsets Get Their Due

In Eastern Cooperative Oncology Group (ECOG) 1594, PS 2 patients did poorly, with a response rate of only 14%, a median survival of 4.1 months, and a 1-year survival rate of only 19%. [18] A high incidence of adverse drug reactions prompted suspension of enrollment on this study, although a later analysis strongly suggested that toxicity overall was little worse in this group compared with PS 0-1 patients. A subsequent ECOG trial (E1599) evaluated the role of attenuated doses of therapy. [19] In this randomized phase 2 effort, patients received paclitaxel 200 mg/m 2 and carboplatin AUC 6 every 3 weeks (PCb; the least toxic arm amongst PS 2 patients enrolled on E1504), or gemcitabine 1 g/m 2 days 1 and 8 in combination with cisplatin 60 mg/m 2 day 1 (GC; the arm with the best median survival [7.9 months] amongst PS 2 participants on ECOG 1594). A total of 103 patients were enrolled. The median age was 66 years; 65% were male; 46% had > 5% weight loss.

Table 2. Paclitaxel/Carboplatin vs Gemcitabine/Cisplatin in PS 2 Patients

	GC	PCb
OR (%)	22	13
OR/SD (%)	51	51
PFS (months)	3.7	3.5
Median survival (months)	6.8	6.1
1-year survival (%)	25	19

GC = gemcitabine 1 g/m 2 days 1 and 8 in combination with cisplatin 60 mg/m 2 day 1; PCb = paclitaxel 200 mg/m 2 and carboplatin AUC 6 every 3 weeks; OR = overall response; SD = stable disease; PFS = progression-free survival

While the GC arm resulted in significantly more grade 3 thrombocytopenia, fatigue, nausea, and grade >/= 1 nephropathy, the PCb arm yielded more grade 3-4 neutropenia, neuropathy, and grade 1 arthralgia/myalgias.

To date, a PS 2-specific, phase 3 trial comparing a single-agent nonplatinating agent vs a combination of platinum and the same single agent has not yet been conducted. In a vested analysis of Cancer and Leukemia Group B (CALGB) 9730, Lilenbaum and colleagues [20] demonstrated therapeutic superiority for paclitaxel and carboplatin compared with paclitaxel alone in the PS 2 cohort, with response rates of 24% and 10%, respectively, median survival rates of 4.7 months and 2.4 months, respectively, and 1-year survival rates of 18% and 10%, respectively.

Using a similar construct, Kosimidis [21] assessed clinical benefit response in PS 2 patients receiving either single-agent gemcitabine 1250 mg/m 2 days 1 and 15 or the combination of gemcitabine at an identical dose and carboplatin AUC 3 every 2 weeks. A total of 102 patients were enrolled; 10 proved ineligible. Median age was 73 years for the single-agent cohort; and 75 years for the combination. The median survival for those receiving single-agent therapy was 4.8 months vs 6.7 months for those receiving combination therapy; 1-year survival rates were 17.8% and 20%, respectively (P = .8), and response rates were 4% and 14%, respectively. The incidence of neutropenia, thrombocytopenia, and anemia was significantly higher for the combination arm. Moreover, there was no difference in symptom improvement rates, strongly suggesting that combination therapy in the salvage setting offers no strategic advantages over the single-agent therapy.

Hesketh and colleagues [22] reported the results of a Southwest Oncology Group (SWOG) trial in both elderly and PS 2 individuals, which assessed the role of sequential single agents, specifically vinorelbine 25 mg/m 2 days 1 and 8 every 3 weeks for 3 cycles followed by docetaxel 35 mg/m 2 days 1, 8, and 15 every month. A total of 44 patients were PS 2; median age in this cohort was 73 years (range, 44-85 years). The response rate in this group was just 10%, median survival time was 4 months, and 1-year survival rate was 14%, possibly inferior to the results observed with combination regimens. In the good PS elderly cohort (n = 75), the median age was 75 years (range, 70-88 years); the response rate was 21%, median survival was 9 months, and 1-year survival rate was 40%. Toxicity proved acceptable in both cohorts, strongly suggesting the utility of this approach in elderly and therapeutically vulnerable patients.

In a similar, phase 2, randomized trial assessing docetaxel given either weekly at 30 mg/m 2 days 1, 8, and 15 given every 4 weeks, or docetaxel every 3 weeks at a conventional dose of 75 mg/m 2 , results were substantially poorer. [23] A total of 42 patients were PS 2, of whom 30 were also over the age of 70 years. Fifty-four were elderly, with intact PS (0-1); 22% were 80 years of age or older; and 85% had stage IV recurrent disease. The weekly approach resulted in significantly more nausea and vomiting (12.5% vs 3%), but less fatigue (6% vs 12%) or diarrhea (0% vs 6%). The response rate overall was 15%, but median survival was dismal: 41 days using the conventional every-3-weeks approach and 91 days using the weekly approach.

Other groups, such as Johnson and colleagues, [24] have assessed the role of single-agent erlotinib in elderly individuals. From March 2003 through December 2003, 36 patients were treated; 30 proved evaluable for toxicity and response. Median age was 76 years (range, 70-86 years); all but 2 had good performance status. The majority (56%) had adenocarcinoma. Only 4 were never smokers. The incidence of grade 3 rash was 8%, although nearly 80% of patients enrolled experienced some degree of rash. Diarrhea occurred in 61%, but proved grade 3 in only 4%; there was 1 case of ILD. Only 9.6% required dose reduction. The overall response rate was 13.3%. These results suggest that single-agent erlotinib is a reasonable option in senior citizens with advanced NSCLC.

By contrast, attempts to graft EGFR-TKI onto conventional chemotherapy in the elderly have led to mixed results. Scagliotti [25] reported the results of a randomized phase 2 effort assessing gefitinib 250 mg daily in combination with either vinorelbine 30 mg/m 2 days 1 and 8 every 3 weeks (arm A) or gemcitabine 1200 mg/m 2 days 1 and 8 every 3 weeks (arm B). A total of 59 patients total were accrued. Arm A was closed early after grade 3/4 adverse events were identified in 87.5% of the first 24 patients accrued; this included a 72% incidence of grade 3/4 neutropenia as well as 3 deaths that appeared to be potentially treatment-related, including 1 grade 5 neutropenia with septic shock and cerebral infarction. In arm A, there was 1 complete response and 3 partial responses; median time to progression was 91 days, and median survival was 371 days, despite toxicity. Arm B featured 3 partial responses; median time to progression was 94 days and median survival was 275 days.

Bronchoalveolar Carcinoma: A Histologic Entity Likely Merits Its Own Trials

Bronchoalveolar carcinoma (BAC) is a distinct clinical, pathologic subtype of adenocarcinoma, with clinical behavior that distinguishes it from other NSCLC histologies. For the most part, during the patient's course, this entity remains confined to lungs; it often progresses slowly, if at all, in a multifocal, infiltrative manner. It tends to occur in younger patients, nonsmokers, and more often in women. BAC also tends to be chemotherapy-resistant, and its incidence is clearly increasing.

West and colleagues [26] reported on the early results of a Southwest Oncology Group (SWOG) trial in which 138 patients were treated with gefitinib 500 mg daily until evidence of progression or prohibitive toxicity. Median age was 68 years (range, 34-88 years). Just over half the patients were female. Response rate by Response Evaluation Criteria in Solid Tumors (RECIST) in chemotherapy-naive patients was 21%, with 6% complete responses. In 21 previously treated patients, the response rate was 9%. Median survival was 12 months and 13 months, respectively, for these 2 cohorts. Stereotypical acneiform rash and diarrhea occurred. A subset analysis showed prolonged survival in women (19 vs 8 months; P = .003) and in patients with rash (13 vs 5 months; P = .01).

In a related presentation, Franklin and colleagues [27] demonstrated an association between activation of ErbB pathway genes and survival. Low ErbB2 levels and pMAPK predicted increased survival in patients with advanced BAC receiving gefitinib. These data strongly suggest that dual inhibition of ErbB1 and ErbB2 could potentially lead to greater therapeutic efficacy.

In a similar phase 2 trial in individuals with BAC, Kris and colleagues [28] reported on the use of erlotinib. A total of 127 patients were enrolled; under central pathologic review, BAC was found in 65%, and 69 ultimately received erlotinib 150 mg daily. Median age was 65 years; 64% were female; 26% had received prior chemotherapy. Only 25% had "pure" BAC, whereas 74% had adenocarcinoma with BAC features. Twenty-nine percent were never smokers. Responses occurred in 7% with pure BAC and in 30% with adenocarcinoma/BAC. The 1-year survival rate was 58%. Of note, never-smokers fared better, with a higher response rate (37%); for those with < 5 pack-years, the RR was 43%, vs 15% in those with >/= 6 pack years.

The results of these phase 2 efforts strongly suggest that BAC may be best pursued with a noncytotoxic approach. Upcoming studies will evaluate the role of cetuximab as well as the combination EGFR-TKIs and vascular inhibiting agents. In addition, the bulk of data to date suggests that those likely to achieve the greatest benefit from EGFR-TKIs are women, nonsmokers, and those with nonsquamous histology.

Conclusions

The role of EGFR-TKIs in the salvage setting was definitively confirmed this year, and the unique nature of BAC, both in terms of its clinical behavior and its sensitivity to targeted agents, was ultimately recognized. It is clear that patients with BAC should probably be segregated from the larger group of NSCLC patients. It is also clear that further headway in the use of targeted agents awaits a better understanding of the molecular pathways that determine both sensitivity and resistance to these agents. Finally, burgeoning data in patients over the age of 70 years and in those with compromised PS show that systemic therapy is both feasible and potentially beneficial to these patients.

References

Shepherd FA, Pereira J, Ciuleanu TE, et al. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. Proc Am Soc Clin Oncol. 2004;23(suppl):18. Abstract 7022.
Perez-Soler R, Chachoua A, Huberman M, et al. A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients (pts) with advanced, EGFR-expressing, non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2001;20:310a. Abstract 1235.
Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2003;21:2237-2246. Abstract
Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290:2149-2158. Abstract
Mohamed MK, Ramalingam S, Lin K, et al. Skin rash and good performance status (PS) predict improved survival with gefitinib for patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:637. Abstract 7097.
Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small cell lung cancer: a phase III trial -- INTACT 1. J Clin Oncol. 2004;22:777-784. Abstract
Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell lung cancer: a phase III trial -- INTACT 2. J Clin Oncol. 2004;22:785-794. Abstract
Janas M, Bailey LR, Schmidt K, et al. Evaluation of epidermal growth factor receptor (EGFR) as a prognostic factor for survival in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy as first-line treatment. Proc Am Soc Clin Oncol. 2004;23:619. Abstract 7024.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139. Abstract
Perez-Soler R, Piperdi B, Haigentz M, Ling Y-H, et al. Determinants of sensitivity to the EGFR TK inhibitor erlotinib (E) in a panel of NSCLC cell lines. Proc Am Soc Clin Oncol. 2004;23:620. Abstract 7026.
Shepherd F, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18:2095-2103. Abstract
Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589-1597. Abstract
Pujol J-L, Shaharyar S, Kortsik C, et al. Post study docetaxel in non-small cell lung cancer (NSCLC) patients after discontinuation from a randomized phase III trial of pemetrexed vs docetaxel: an explanatory analysis. Proc Am Soc Clin Oncol. 2004;23:647. Abstract 7135.
De Marinis F, Pereira JR, Park K, et al. Does second-line therapy for non-small cell lung cancer (NSCLC) result in symptoms palliation? Analysis of 484 patients from a randomized trial of pemetrexed vs docetaxel. Proc Am Soc Clin Oncol. 2004;23:622. Abstract 7035.
Schuette W, Nagel S, Serke M, et al. Second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) with weekly versus three-weekly docetaxel: results of a randomized phase III study. Proc Am Soc Clin Oncol. 2004;23:622. Abstract 7036.
Takeda K, Negoro S, Tamura T, et al. Docetaxel (D) versus docetaxel plus gemcitabine (DG) for second-line treatment of non-small cell lung cancer (NSCLC): results of a JCOG randomized trial (JCOG0104). Proc Am Soc Clin Oncol. 2004;23:622. Abstract 7034.
Pectasides D, Farmakis D, Pectasides M, et al. Docetaxel versus docetaxel plus irinotecan as second line chemotherapy in advanced non-small cell lung cancer (NSCLC): a randomized phase II trial. Proc Am Soc Clin Oncol. 2004;23:621. Abstract 7033.
Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic non-small cell lung carcinoma. Cancer. 2001;92:2639-2647. Abstract
Tester WJ, Stephenson P, Langer CJ, et al. ECOG 1599: Randomized phase II study of paclitaxel/carboplatin or gemcitabine/cisplatin in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:627. Abstract 7055.
Lilenbaum RC, Herndon J, List M, et al. Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): a CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol. 2002;21:1a. Abstract 2.
Kosimidis PA, Dimopolous MA, Syrigos C, et al. Gemcitabine (G) vs gemcitabine-carboplatin (GCB) for patients with advanced non-small cell lung cancer (NSCLC) and PS2: A prospective randomized phase II study of the Hellenic Co-Operative Oncology Group. Proc Am Soc Clin Oncol. 2004;23:627. Abstract 7058.
Hesketh PJ, Chansky K, Lau DK, Crowley J, Gandara DR. Sequential vinorelbine (V) and docetaxel (D) in advanced non-small cell lung cancer (NSCLC) patients age > 70, or with performance status (PS) 2: A SWOG phase II trial (S0027). Proc Am Soc Clin Oncol. 2004;23:627. Abstract 7056.
Lilenbaum R, Rubin M, Samuel J, et al. A phase II randomized trial of docetaxel weekly or every 3 weeks in elderly poor performance status (PS) patients (pts) with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:627. Abstract 7057.
Johnson BE, Lucca J, Rabin MS, et al. Preliminary results from a phase II study of the epidermal growth factor erlotinib in patients > 70 years of age with previously untreated advanced non-small cell lung cancer. Proc Am Soc Clin Oncol. 2004;23:633. Abstract 7080.
Scagliotti G, Rossi A, Novello S, et al. Gefitinib (ZD1839) combined with gemcitabine or vinorelbine as single-agent in elderly patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:633. Abstract 7081.
West H, Franklin WA, Gumerlock PH, et al. Gefitinib (ZD1839) therapy for advanced bronchioloalveolar carcinoma (BAC): Southwest Oncology Group (SWOG) study S0126. Proc Am Soc Clin Oncol. 2004;23:618. Abstract 7014.
Franklin WA, Chansky K, Gumerlock PH, et al. Association between activation of ErbB pathway genes and survival following gefitinib treatment in advanced BAC (SWOG 0126). Proc Am Soc Clin Oncol. 2004;23:618. Abstract 7015.
Kris MG, Sandler A, Miller V, et al. Cigarette smoking history predicts sensitivity to erlotinib: results of a phase II trial in patients with bronchioloalveolar carcinoma (BAC). Proc Am Soc Clin Oncol. 2004;23:628. Abstract 7062.

Authors and Disclosures

As an organization accredited by the ACCME, Medscape requires authors and editors to disclose any significant financial relationship during the past 12 months with the manufacturer of any product that may relate to the subject matter of the educational activity, whether or not the activity is commercially supported. Authors are also asked to disclose any mention of investigational products or unapproved uses of products regulated by the U.S. Food and Drug Administration.

Authors

Corey J. Langer, MD, FACP
Associate Professor, Medical Director, Thoracic Oncology, Temple University; Medical Director, Thoracic Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Disclosure: Corey J. Langer, MD, FACP, has disclosed that he received grants or research support from Bristol-Myers Squibb, Pharmacia, Eli Lilly, Schering-Plough Research Institute, Aventis, Amgen, Cell Therapeutics Inc., OrthoBiotech, Celgene, Vertex, Genentech, AstraZeneca, Pfizer, Active Biotech, and Medimmune. Dr. Langer has served as a scientific advisor for Bristol-Myers Squibb, ImClone, Aventis, Pharmacia, Intrabiotics, GlaxoSmithKline, Pharmacyclics, Amgen, AstraZeneca, Genentech, Sanofi-Synthelabo, and Novartis. He has served on the Speaker's Bureau for Bristol-Myers Squibb, Aventis, Pharmacia, Eli Lilly, and OrthoBiotech. Dr. Langer reported that he discusses the investigational uses of erlotinib and cetuximab and the unlabeled uses of pemetrexed and gefitinib in the treatment of lung cancer.

Thomas J. Lynch, MD
Associate Professor of Medicine, Harvard Medical School; Director of Thoracic Malignancy, Massachusetts General Hospital, Boston, Massachusetts

Disclosure: Thomas J. Lynch, MD, has disclosed that he has received grants for clinical research from Lilly, AstraZeneca, Genentech, and SmithKline Beecham. Dr. Lynch has received grants for educational activities from Lilly and AstraZeneca. He has served as an advisor or consultant for Lilly, Aventis, Genentech, and SmithKline Beecham. Dr. Lynch has received honoraria for speaking from AstraZeneca. He has reported that he does not discuss any investigational or unlabeled uses of commercial products in this activity.

Clinical Editors

Shira Berman
Site Editor, Medscape Hematology-Oncology

Disclosure: Shira Berman has no significant financial interests or relationships to disclose.

The "C" Word (no, not that one)

((((wuzzy))))

American Society of Clinical Oncology 2004 Annual MeetingManagement of Lung Cancer CME

Target Audience

Goal

Overall Learning Objectives

Learning Objectives for this CME Activity

Contents of This CME Activity

Management of Early-Stage and Locally Advanced Non-Small-Cell Lung Cancer

Adjuvant Chemotherapy Comes of Age: CALGB and National Cancer Institute of Canada Studies Provide Strong Evidence of Benefit

Table 1. Patient Characteristics and Results of CALGB 9633

Table 2. Patient Characteristics and Results of National Cancer Institute of Canada BR10

Two Cycles of Induction Chemotherapy Fail to Improve Outcome for Patients With Locally Advanced NSCLC

Table 3. Patient Characteristics and Results of CALGB 39801

Table 4. Summary of Trials in Locally Advanced NSCLC

Stereotactic Radiotherapy Offers Option for Early-Stage NSCLC

References

Advanced Non-Small-Cell Lung Cancer: Focus on Treatment-Naive Patients

Chemotherapy Plus Targeted Therapies in Treatment-Naive Advanced NSCLC

Table 1. Paclitaxel/Carboplatin ± Erlotinib in Advanced NSCLC (TRIBUTE)

Table 2. Gemcitabine/Cisplatin ± Erlotinib in Advanced NSCLC (TALENT)

Conventional Cytotoxic Approaches in Treatment-Naive, Late-Stage NSCLC

Table 3. Four-arm Study of Chemotherapy Regimens in Treatment-Naive Advanced NSCLC

Table 4. Carboplatin + Paclitaxel Weekly or Once Every 3 Weeks in Treatment-Naive Advanced NSCLC

References

Advanced Non-Small-Cell Lung Cancer: Focusing on the Therapeutic Horizon in 2004

Salvage Therapy: The Redemption of EGFR-TKI

Table 1. Erlotinib vs Best Supportive Care in NSCLC in the Salvage Setting

Molecular and Clinical Prognostic Factors for EGFR-TKIs

Defining the Optimal Regimen in the Second- and Third-Line Settings

Special Populations: Neglected Subsets Get Their Due

Table 2. Paclitaxel/Carboplatin vs Gemcitabine/Cisplatin in PS 2 Patients

Bronchoalveolar Carcinoma: A Histologic Entity Likely Merits Its Own Trials

Conclusions

References

Authors and Disclosures

Authors

Corey J. Langer, MD, FACP

Thomas J. Lynch, MD

Clinical Editors

Shira Berman

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American Society of Clinical Oncology 2004 Annual Meeting
Management of Lung Cancer CME