Minimal Progress, Potential Promise in Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers diagnosed in the United States. It is characterized by initial sensitivity to chemotherapy, but a rapid progression to refractory disease and death in a majority of patients. Minimal progress has been achieved in the past several years in the treatment of patients with SCLC. The paper by Drs. Hann and Rudin, published in this issue of the journal, is a comprehensive review of the diagnosis and management of small-cell lung cancer, and also provides insight into ongoing research efforts.

New Staging System
As the authors illustrate, SCLC is broadly staged as either “limited” or “extensive.” This categorization has helped physicians choose the optimal treatment approach for patients with SCLC. Recent efforts by the International Association for Study of Lung Cancer (IASLC) to develop a new staging system for lung cancer have led to a few interesting observations.[1] Among patients with SCLC (approximately 12,000 in the database), significant differences in outcome were noted between patients with various T stages in the absence of metastatic disease. Similarly, differences in outcome were noted between patients with N0/N1 disease and those with N2/N3. Based on these findings, the staging committee has recommended the use of the tumor-node-metastasis (TNM) classification for SCLC as a standard approach. The use of the TNM system will provide more accurate prognostic information about patients with SCLC. In other words, even among patients with limited-stage disease, it will be possible to identify subsets with a more favorable outcome. It also underscores the need to stratify patients based on the T and N stage in clinical trials for limited-stage disease in order to eliminate differences in outcome based on stage alone.

As such, the new system is unlikely to change the management of patients for the immediate future. Chemotherapy with radiation will continue to be used for patients with disease confined to one hemithorax with or without contralateral nodal involvement. The management of patients with a pleural effusion continues to be a challenge, since some studies in limited-stage disease have included this subgroup. In the new staging project, the outcome for patients with pleural effusion (cytologically positive or negative) was intermediate to those with limited and extensive stages of the disease.

Radiotherapy for Limited-Stage Disease
For patients with limited-stage disease, administration of platinum-based chemotherapy with concurrent thoracic radiation is the standard approach. The role of thoracic radiation in limited-stage disease is now well established following the meta-analysis conducted by Pignon et al, who demonstrated a 5% survival advantage at 3 years and an improvement in local control.[2] Though the use of twice-daily fractions (45 Gy) of radiation is the evidence-based method, it has not gained popularity among physicians in the United States and many other parts of the world. This has largely been due to logistical challenges. As an alternative, in routine practice, many radiologists use a once-daily fraction of approximately 60 to 70 Gy, which is considered to be biologically equivalent to the 45 Gy twice-daily regimen.

Recently, a phase III study was initiated to compare the two radiation schedules (45 Gy twice daily vs 70 Gy once daily) in combination with chemotherapy for patients with limited-stage disease. This study will also evaluate a third regimen consisting of a combined strategy of daily dosing initially followed by twice-daily administration for the last 2 weeks (total of 61.2 Gy). The results of this ongoing study will help to determine the optimal radiation therapy strategy for patients with limited-stage SCLC. It is hoped that improvements in local control will lead to better disease control and a higher survival rate.

Systemic Treatment
The Hann/Rudin paper also illustrates the challenges involved in systemic treatment of patients with SCLC. Though a number of novel approaches such as alternating cycles of two regimens, high-dose therapy, dose-intense therapy, and three-drug combinations have all been studied, the results have been consistently disappointing. The combination of cisplatin and etoposide administered for four cycles remains the standard therapy in the United States. The regimen of cisplatin and irinotecan, although efficacious in the Japanese patient population,[3] failed to demonstrate a survival advantage over cisplatin/etoposide in two phase III studies conducted outside of Japan.[4,5]

Topotecan, a topoisomerase inhibitor, is efficacious in both front-line therapy (in combination with cisplatin) and for patients with sensitive relapse. It is now available in an oral formulation, which may increase convenience for patients, but this could hardly be viewed as progress. Recently, the anthracycline derivative amrubicin demonstrated robust response rates in patients with refractory and relapsed disease. Confirmation of these results in phase III studies is eagerly awaited.

Targeted Therapy
Several studies have evaluated the addition of a molecularly targeted agent to combination chemotherapy for patients with extensive-stage SCLC. The addition of bevacizumab (Avastin) to chemotherapy or administration of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors in the maintenance setting or in relapsed disease have not been successful. It is clear that the situation calls for evaluation of newer classes of anticancer agents for the treatment of SCLC.

The Hann/Rudin paper describes some of the promising agents-such as inhibitors of the insulin-like growth factor receptor (IGF-1R) pathway and the hedgehog pathway-that are currently under clinical evaluation for the treatment of SCLC. Another targeted strategy under evaluation involves the use of histone deacetylase inhibitors in combination with standard agents. This is based on observations that epigenetic modulation through DNA methylation and histone deacetylation may play a role in the clinical and biologic progression of the disease.

From the experience to date with targeted agents, it is difficult to understand whether the failures were due to the pursuit of the wrong targets or inadequate modulation of the target. The high rate of genetic instability in small-cell lung cancer might result in significant redundancy in signaling pathways such that the cancer cells are no longer dependent on any one specific target. Of course this is speculative, but future clinical trials of biologic or targeted agents should be undertaken after a robust demonstration in the preclinical setting that the cancer is dependent on the targeted pathway(s) or mechanism(s), and that abrogating that pathway produces demonstrable tumor regression.

Finally, the importance of enrolling patients in novel clinical trials to accelerate drug discovery efforts cannot be overemphasized.

References:

1. Shepherd FA, Crowley J, Van Houtte P, et al: The International Association for the Study of Lung Cancer lung cancer staging project: Proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2:1067-1077, 2007.

2. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618-1624, 1992.

3. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85-91, 2002.

4. Hanna N, Bunn PA Jr, Langer C, et al: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:2038-2043, 2006.

5. Natale RB, Lana PN, Chansky K, et al: S0124: A randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated extensive stage small cell lung cancer (E-SCLC) (abstract 7512). J Clin Oncol 26(15S):400s, 2008.