IASLC 2011 Report – Recent developments in the management of small cell lung cancers

by Dr Sunil Upadhyay – The incidence of small cell lung cancer accounts for nearly 15% of all diagnosed lung cancers. The majority present with locally advanced disease and/or distant metastasis. It is estimated that roughly 2/3 of the patients have extensive disease. Surgery has little role but chemotherapy has a crucial role in the management of small cell lung cancers, even at early stage. Over the last three decades the chemotherapy regimen remains similar, hence little improvement on survival due to chemotherapy can be attributed for this disease. The 2-year survival rate among patients with extensive disease was 1.5% in 1973 and 4.6% in 2000.¹ Other than better staging, it will not be incorrect to say that most of the improvements in survival for patients with small cell lung cancer have been achieved mainly due to the developments in radiotherapy techniques used as an adjuvant therapy with chemotherapy. Adjuvant use of consolidation radiotherapy for the thoracic disease and prophylactic cranial irradiation (PCI) to control the brain micro-metastasis has become the gold standard evidence-based treatment at least for early stage tumours. It not only helps to control the disease but also improves the survival. Meta-analysis revealed a survival benefit for small cell lung cancer treated with PCI, with a 3-year survival rate of 20.7% among patients who underwent irradiation and 15.3% among those who did not.^2,3The magnitude of this survival benefit is similar to that achieved with the use of thoracic radiotherapy in patients with limited stage.

The incidence of brain micro-metastasis is considered to be higher in patients with extensive disease. Therefore, it is natural to consider PCI in patients with extensive disease following good extra-cranial response from primary chemotherapy. The EORTC trial result showed that the cumulative risk of symptomatic brain metastasis was 14.6% with PCI and 40.4% with the control group at 1 year with significant PFS and median overall survival benefits.⁵ In this trial, the one-year survival rate was 27.1% with PCI compared to 13.3% in the control arm. Although the irradiation had side effects it did not have a clinically significant effect on the global health status. NICE guidelines recommend PCI for patients with PS 0-2 if their disease has not progressed on first line treatment. Similarly concurrent thoracic radiotherapy has been found to improve median survival in a selected group of patients from 11 to 17 months in patients with a complete response after three cycles of chemotherapy. The overall survival was 22% at 3 years and 9% at 5 years for the radiotherapy group and 13% at 3 years and 4% at 5 years for the chemotherapy alone group of patients.⁶ These results are encouraging and validation of these results in further studies is necessary before final recommendation. With the development of advanced radiotherapy techniques, optimal radiotherapy dose, volume and timing have to be defined.

Platinum-based combination chemotherapy remains the cornerstone of the treatment of small cell lung cancer, with very little progress since 1980. Various approaches like dose-dense, high-dose and alternating regimens of chemotherapy have all failed to improve the relapse rate and survival. Targeted agents have also been found to be inactive in tumours with this histology with or without cytotoxic therapy. Relapse is common and topotecan has been found to show some activity in chemotherapy-sensitive disease. It was found to be associated with better symptom control compared to cyclophosphamide, doxorubicin and vincristine triplet but hardly any survival advantage. After the initial promising response seen with amrubicin in a phase II trial, Phase III trial results of amrubicin versus topotecan as second-line treatment was presented by J. von Pawel at WCLC 2011.

Phase III second-line SCLC: ACT-1 Trial

Primary end point: Overall survival

Secondary endpoint: ORR, PFS, TTP, LCSS, QoL and safety

 

The median age was 62/61 years with both arms well balanced. The primary endpoint of overall survival in intention to treat (ITT) was not significantly different (7.5 months with amrubicin vs. 7.8 months with topotecan; HR=0.880 and p=0.1701) between the two groups. However, all the secondary endpoints favoured amrubicin. The overall response rate was 31.1% vs. 16.9% (p 0.0001), median PFS was 4.1 months vs. 3.5 months (HR=0.802, p=0.0182) with improved symptom control favouring amrubicin. An improvement in overall survival in refractory patients was observed (6.2 month with amrubicin vs. 5.7 months with topotecan, HR=0.766, p=0.0469). The safety profile of amrubicin was acceptable, with increased incidence of infections but fewer blood transfusions. It is important to note that almost all patients included in this trial were highly selected with good performance status (0, 1), anthracycline naïve and a high proportion of (45%) refractory tumours. Clearly, the overall survival and the median survival were similar in patients receiving either drug indicating non-superiority, although the response rate was slightly better with amrubicin. The late separation of the survival curve could be due to post-progression therapy. Cost comparison with CAV regimen and role of re-challenge with platinum doublet at least in sensitive patients are the other barriers to prevent the use of amrubicin in the NHS clinics. (Abstract O01.02).

 

References:

1. Govindan R, Page N, Morgensztern D et al. J Clin Oncol  2006; 24: 4539-4544

2. Auperin A, Pignon J-P, Le Péchoux C, Gregor A et al. NEJM; 1999; 341: 476-484

3. Meert AP, Paesman M, Berghmans T, Martin B, Mascaux C et al. BMC Cancer  2001; 1:5

4. Pignon J P, Arriagada R, Ihde DC, Johnson DH, Perry MC et al. NEJM 1992; 327: 1618-1624

5. Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M et al. NEJM 2007; 357: 664-672

6. Jeremic B, Shibamoto Y, Nikolic N, Milicic B, Milisavljevic S et al. JCO 1999; 17: 2092-2099