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Published on 21 September 2007

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Latest advances in the treatment of small-cell lung cancer

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Fiona H Blackhall
BSc MBChB MRCP PhD

Consultant Medical Oncologist and Honorary Senior Lecturer

Department of Medical Oncology

Christie Hospital NHS Foundation Trust and Manchester University
Manchester
UK

E: Fiona.Blackhall@christie.nhs.uk

The median survival of untreated SCLC is only two to four months due to a rapid ­cancer cell doubling time, early dissemination and metastasis. Treatment is based on whether the disease is limited-stage (LS), defined as tumour confined to the hemithorax of origin and which can be encompassed within a radiation therapy port, compared with extensive-stage (ES), defined as too widespread to be included within the definition of LS disease, usually due to the presence of extra‑thoracic metastases.(1) During the 1970s response rates exceeding 80% were observed in patients with LS and ES SCLC with platinum and etoposide (PE) and anthracycline-based regimens.(2,3) During the 1980s and 1990s, anthracycline-based ­regimens – ­adriamycin, cyclophosphamide and etoposide (ACE), cyclophosphamide, adriamycin and ­vincristine (CAV) and cyclophosphamide, epirubicin and ­vincristine (CEV) – were favoured, particularly in Europe, whereas evidence now points in favour of PE. A Norwegian trial conducted in 436 patients demonstrated superior survival for PE compared with CEV among patients with LS SCLC, and also revealed a trend towards better survival among patients with ES SCLC for PE.(4) Other reports have confirmed less myelosuppression for PE.(5,6) With PE, patients with ES SCLC can expect a median survival of 6–12 months, whereas patients with LS SCLC can expect median survivals of 16–24 months and a prospect of cure with the addition of thoracic and prophylactic cranial radiotherapy (PCI).(7,8) Evidence to suggest that early thoracic radiotherapy delivered with the first or second cycle of chemotherapy is superior to later radiotherapy sequential to chemotherapy(9) is promoting a general trend towards concurrent chemo‑radiotherapy treatment for LS SCLC. However, concurrent treatment is associated with increased morbidity; therefore, patient selection and administration requires close collaboration between medical and radiation oncologists, with prompt supportive management of haematological, oesophageal and pulmonary toxicities. A current goal is to optimise thoracic radiotherapy and potentially improve on local control rates. One randomised study demonstrated a five-year survival rate of 26% in patients treated with twice-daily radiation therapy (45 Gy) given over three weeks, compared with a rate of 16% with once-daily radiation therapy (45 Gy) given over five weeks.(10) However, delivery of a higher total dose of radiotherapy may improve further on these results. The upcoming CONVERT trial will evaluate a dose of 66 Gy delivered once daily over six weeks compared with the twice-daily schedule. The role of PCI to prevent intracranial relapse in patients with LS SCLC is well established.(11) Until now PCI has not been administered to patients with ES ­disease, despite a high frequency of brain metastases in this population. This year convincing evidence for PCI in ES SCLC emerged from a ­European study ­conducted in 286 patients. PCI reduced risk of developing symptomatic brain metastases by 73% and also improved one-year survival substantially, from 13% in the control group to 27% in the PCI group.(12)

Second-line treatment
In the majority of patients, SCLC relapses within months to one year of initial treatment. Patients who have sensitive relapse, defined as progression >3 months after treatment, are frequently ­rechallenged with the same treatment that was used first-line or with a different regimen such as CAV. Until recently, evidence for a benefit from second-line therapy was anecdotal. A UK trial ­provided proof for second-line chemotherapy over best supportive care using oral topotecan.(13) Prior to this result, a phase III trial comparing topotecan with CAV gave similar response and survival rates. Symptom ­control was improved on topotecan at the expense of increased toxicity.(14) With no clear “best” treatment, choice of second-line agent is currently guided by prior treatment, drug cost, treatment schedule and toxicity profile.(15)

New approaches
Irinotecan and cisplatin appeared promising in a ­Japanese study for patients with ES SCLC that demonstrated a significantly better median ­survival of 12.8 months for this regimen vs 9.4 months for PE.(16) However, a similar trial conducted in a ­Western ­population revealed no survival difference.(17) Other ­trials are ongoing(18) and it appears feasible to ­combine radiotherapy with irinotecan and ­cisplatin.(19) Results from trials of gemcitabine in SCLC have been ­generally disappointing, with lower-than-expected response rates and survival for ­gemcitabine and cisplatin,(20) and irinotecan with gemcitabine.(21) ­Amrubicin, a ­synthetic 9-amino‑anthracycline, has significant antitumour ­activity in Japanese patients(22) and studies to evaluate the drug in patients with ES SCLC in the USA and Europe are ongoing.(18) The multitargeted antifolate pemetrexed ­combined with carboplatin is currently being ­compared with ­carboplatin and etoposide in a phase III trial, ­following ­promising phase II data.(23) The pemetrexed/­carboplatin ­regimen is predicted to be less toxic with a more ­convenient schedule for administration (1–2 hour infusion every three weeks) compared with PE that is administered daily for three days every three weeks. An ­increasing number of targeted ­therapies is undergoing ­evaluation in SCLC. Notably, the French ­Intergroup demonstrated in a ­randomised phase II trial a median survival of 11.7 months for thalidomide in combination with a four-drug chemotherapy ­regimen, compared with 8.7 months for chemotherapy with placebo.(24) ­Toxicity was a ­significant factor but these results are the first evidence that antiangiogenesis may be a ­viable strategy for SCLC. Results from a phase III trial of thalidomide or ­placebo in combination with PE ­conducted by the London Lung Cancer Group will be presented at the 12th World Conference on Lung Cancer, to be held in Seoul, South Korea, this year. Trials are ­ongoing, aiming at evaluating the licensed antiangiogenic bevacizumab in addition to other agents designed to target growth factor receptor signalling pathways and promote apoptosis.(25)

Conclusion
An increasing number of agents, both cytotoxic and targeted, and new radiotherapy schedules, are now under active investigation for SCLC. Existing regimens such as PE and CAV are effective in first-line treatment; in addition, they are inexpensive and have not been surpassed for three decades. When a breakthrough for a new therapy occurs, cost-­effectiveness considerations may pose a significant barrier to the adoption of new therapies for some health economies. Nevertheless, given the dismal prognosis for the majority of patients with SCLC, clinical research aiming to improve outcomes should be of highest priority.

References
1. Chest 1986;89(4 Suppl):225-33S.
2. JAMA 1976;235(12):1225-9.
3. Cancer Treat Rep 1979;63(9-10):1593-7.
4. J Clin Oncol 2002;20(24):4665-72.
5. J Natl Cancer Inst 1991;19;83;12:855-61.
6. J Clin Oncol 1992;10(2):282-91.
7. N Engl J Med 1992;3;327(23):1618-24.
8. J Clin Oncol 1992;10(6):890-5.
9. J Clin Oncol 2006;1;24(7):1057-63.
10. N Engl J Med 1999;28;340(4):265-71.
11. N Engl J Med 1999;12;341(7):476-84.
12. N Engl J Med 2007 Aug 16;357(7):664-72.
13. J Clin Oncol 2006;24(34):5441-7.
14. J Clin Oncol 1999;17(2):658-67.
15. J Thorac Oncol 2007;2(4):348-54.
16. N Engl J Med 2002;346(2):85-91.
17. J Clin Oncol 2006 May 1;24(13):2038-43.
18. US National Institutes of Health. ClinicalTrials.gov. Bethesda MD: NIH; 2007. Available at: www.clinicaltrials.gov
19. Cancer 2007;109(9):1845-950.
20. J Thorac Oncol 2007;2(5):440-4.
21. J Thorac Oncol 2007;2(6):526-30.
22. Invest New Drugs 2007;25(3):253-8.
23. Expert Rev Anticancer Ther 2007;7(5):635-40.
24. J Clin Oncol 2006;1;24;18S:17089.
25. Curr Opin Oncol 2007;19(2):103-8.

Resources
The NIH treatment statement for health professionals on small-cell lung cancer provides an up-to-date summary and is regularly updated
W: www.meb.uni-bonn.de/cancer.gov/CDR0000062945.html

Cancer Care Ontario produces standards and guidelines that include chemotherapy dosing and administration
W: www.cancercare.on.ca/index_standards.htm



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