|Year : 2008 | Volume
| Issue : 6 | Page : 100-103
|Treatment for small-cell lung cancer
Ahmed Saadeen1, Abdul-Rahman Jazieh2
1 Riyadh Military Hospital, Riyadh, Saudi Arabia
2 King Abdulaziz Medical City, Riyadh, Saudi Arabia
Department of Oncology (Bldg 1), Riyadh Military Hospital, P.O. Box 7897, Riyadh 11159
| Abstract|| |
Small-cell lung cancer (SCLC) accounts for 13-20% of all lung cancers. Stongly associated with smoking and initially responsive to treatment, it results in death within 2-4 months without treatment. Limited-stage disease is treated with curative intent with chemotherapy and radiation therapy, with approximately 20% of patients achieving a cure. Extensive-stage disease is primarily treated with chemotherapy and has a high initial response rate of 60-70% but the median survival is only 10 months. All patients achieving a complete remission should be offered prophylactic cranial irradiation. Relapsed or refractory SCLC has a uniformly poor prognosis.
Keywords: Small cell lung cancer, treatment, radiation, chemotherapy
|How to cite this article:|
Saadeen A, Jazieh AR. Treatment for small-cell lung cancer. Ann Thorac Med 2008;3, Suppl S2:100-3
| Introduction|| |
Since the 1980s, systemic cisplatin-based combination chemotherapy has emerged as the cornerstone of treatment for this disease, resulting in a significant improvement in overall survival.
During the 1990s it became clear that the addition of radiation therapy for the primary tumor as well as the mediastinum improved local control and thus led to a significant long-term survival benefit for patients with SCLC and this was proven in a large meta-analysis of prospective randomized trials available at that time.
There is a high incidence of brain metastases, amounting to 80% at 2 years. Due to poor response to systemic therapy, it is recommended to use prophylactic cranial irradiation (PCI) to improve survival in patients in complete remission as PCI has been proved to significantly reduce the risk of symptomatic brain metastases.
It is quite clear that improving the survival of patients with SCLC requires a better understanding of tumor biology and the development of novel therapeutic strategies. Several targeted agents have been introduced into clinical trials.
This manuscript reviews the current treatment of this disease and the future prospects.
| Epidemiology|| |
The proportion of SCLC (among all histological types of lung cancer) in the Kingdom of Saudi Arabia was 12.0% in males and 1.2% in females (National Cancer Registry 2003 Report, Kingdom of Saudi Arabia). In the USA, the proportion of SCLC decreased from 17% in 1986 to 13% in 2003.
A modest but statistically significant improvement in 2- and 5-year survival has been noted with the currently accepted treatment of SCLC.
| Staging|| |
Routine staging of SCLC includes the following: complete clinical history and physical examination, complete blood count and comprehensive chemistry panel, CT of the chest and abdomen, CT or MRI of the brain, and bone scan. Positron emmission tomography (PET) scan is not routinely recommended.
The TNM staging system for lung cancer is not commonly employed in patients with SCLC. For the purpose of treatment, patients with SCLC are classified as having either limited disease or extensive disease.
In limited-stage disease the malignancy is confined to one hemithorax within a tolerable radiation field; it can be divided into two subgroups:
- Very limited disease: when disease is confined to one hemithorax without mediastinal lymph node involvement.
- Limited disease: when disease is confined to one hemithorax but involves the contralateral lymph nodes (all within the radiation field) [Figure 1].
There is no universally accepted definition of the term 'limited-stage.' For example, patients with pleural effusion, a massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from 'limited-stage' by various groups.
Extensive-stage SCLC means that the tumor that is too widespread to be included within the definition of limited-stage disease as described above. Patients with distant metastases (M1) are always considered to have extensive-stage disease [Figure 2].
| Prognostic Factors|| |
The prognostic factors that predict prolonged survival include: good performance status, female gender, and limited-stage disease. Patients with CNS or liver involvement at diagnosis have a poor outcome.
| Pathologic Classification|| |
Neuroendocrine carcinomas of the lung represent a spectrum of disease. At one extreme is SCLC, which has a poor prognosis; at the other extreme are bronchial carcinoids, which have an excellent prognosis after surgical excision
Careful diagnosis is important, since the differential pathologic diagnosis from SCLC may be difficult; it is therefore very important to ensure review of pathologic material by an experienced lung cancer pathologist before starting treatment.
The current classification of subtypes of SCLC is as follows:
- Small-cell carcinoma
- Mixed small-cell / large-cell carcinoma
- Combined small-cell carcinoma (i.e., SCLC combined with non-small cell lung cancer (NSCLC))
Patients with mixed SCLC / NSCLC histology should be treated similar to patients with SCLC
| Treatment Overview|| |
Very-limited-stage disease can be considered for curative-intent surgical resection; invasive mediastinal staging and extrathoracic imaging (i.e., brain CT / MRI, abdominal CT, and bone scan) should be performed in all patients.
Platinum-based adjuvant chemotherapy is recommended. PCI should be offered for postresection patients.
For limited-stage disease, treatment has a small but definitively curative intent. The 5-year survival is about 10-25%. Combination chemotherapy is the backbone of treatment:
- Cisplatin 80 mg/m 2 D1 and etoposide 120 mg/m 2 D1-3
- Carboplatin AUC 5-6 and etoposide 100 mg/m 2 D1-3
The cycles are repeated every 3 weeks for 4 cycles.
Thoracic radiotherapy significantly improves long-term survival. ,,,, Twice-daily radiotherapy gives better local control and better long-term survival than once-daily treatment. A total of 45 Gy is delivered as 1.5 Gy/fraction, twice daily, for 3 weeks. With this regimen the 5-year survival is 26% vs. 16% when once-daily treatment is given.
An alternative is the conventional fractionation to a total dose of 50-60 Gy, delivered as 1.8-2 Gy/fraction, once daily; but this treatment has possibly less benefit.
Concurrent early chemoradiotherapy gives better results than late radiotherapy. Cisplatin and etoposide are recommended with concurrent chemoradiation protocols. The additional benefit in survival outcome can predominantly be attributed to the better local control.
Patients achieving a complete remission should be offered PCI. It improves survival by 4-5% at 5 years.
Patients with extensive-stage disease should receive 4 to not more than 6 cycles of platinum-based combination chemotherapy. ,,,,, The following regimens produce similar survival outcomes:
- EP or EC: etoposide + cisplatin or carboplatin
• 100 mg/m 2 D1-3, 75 mg/m 2 D1 or AUC5, respectively
- CAV: cyclophosphamide + doxorubicin + vincristine.
• 1000 mg/m 2 D1, 45 mg/m 2 D1 and 1.4 mg/m 2 , consecutively
- CAE: cyclophosphamide + doxorubicin + etoposide
• 1000 mg/m 2 D1, 45 mg/m 2 D1 and 100 mg/m 2 D1-3 consecutively
- ICE: ifosfamide + carboplatin + etoposide 
• 2 gm/m 2 D1 and 2, 300 mg/m 2 , D1, 100 mg/m 2 D1-3, consecutively
- Cisplatin + irinotecan
• 60 mg/m 2 D1 and 60 mg/m 2 D1, 8, and 15, consecutively
Patients who achieve a complete remission should be offered PCI, and patients achieving a complete response (CR) outside the chest and complete or partial response in the chest could be offered consolidative thoracic radiation therapy to the chest.
Radiation therapy is recommended to sites of metastatic disease which are unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases.
Prophylactic cranial irradiation (PCI) 
There is a high incidence of brain metastases in SCLC: 18% at diagnosis and up to 80% at 2 years. This has triggered a number of prospectively randomized investigations of PCI in this clinical setting, predominantly targeting patients in complete remission after initial therapy.
When individual patient data from randomized trials were combined in a meta-analysis, it was established that PCI adds approximately 5% at 3 years to the long-term cure rates of these patients. 
This treatment is well tolerated and does not adversely influence overall health status. The usual dosing is 30 Gy given in 15 fractions over 3 weeks period using 3D conformal radiotherapy when available.
Surgery in the treatment of SCLC
Based on the historical experience, surgery has been utilized only in early-stage disease. The majority of trials occurred in the 1980s and did not include a platinum-based chemotherapy regimen. The long-term survival results of treatment with combinations of chemotherapy and surgery were not convincing.
In 1990, with modern concurrent chemoradiation protocols available, prospective data on the addition of surgery to the combined modality treatment of SCLC are limited; however, in carefully selected patients this should be encouraged. This strategy may result in an impact comparable to that demonstrated by the Intergroup 0139 trial in locally advanced NSCLC.
For recurrent SCLC, the response to first-line therapy is more than 60%, with more than 95% relapsing after first-line treatment.
Second-line treatment is often considered to be part of palliation. Although palliative radiation therapy should always be considered, local palliation with endobronchial laser therapy, endobronchial stents, and / or brachytherapy is also frequently used.
The following are useful guidelines to the use of palliative chemotherapy:
If relapse occurs within 3 months of primary treatment, the taxanes, gemcitabine or ifosfamide, can be considered. For relapse occurring between 3-6 months of primary treatment, topotecan or an irinotecan-based regimen should be considered.  The original regimen can be considered if relapse has occured more than 6 months after primary treatment. ,,,,,,,,
Targeted therapy for SCLC
The development of targeted therapy for SCLC has lagged behind that of NSCLC. Several targeted agents have been introduced into clinical trials in SCLC and some phase III studies have already produced definitive results. Most of the studied agents are either ineffective or have marginal activity.
Current drugs under investigation include those targeting the angiogenetic, apoptotic, and mammalian target of rapamycin (mTOR) pathways. Vaccines could be among the promising therapies under development.
To date, no targeted therapy has been approved for use in the treatment of patients with SCLC.
Treatment summary of SCLC
For limited disease
Early concurrent chemoradiotherapy for limited-stage SCLC. The cisplatin-etoposide chemotherapy combination is the best among the regimens that has been tested. PCI should be offered for complete responders. Surgery is rarely used in the management of this disease.
For extensive disease
Platinum-based chemotherapy is the cornerstone of treatment. Second-line therapy should be considered when appropriate. PCI should be considered for good responders.
| References|| |
|1.||Feld R, Evans WK, DeBoer G, Quirt IC, Shepherd FA, Yeoh JL, et al . Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung. J Clin Oncol 1984;2:294-304. [PUBMED] [FULLTEXT]|
|2.||Greco FA, Richardson RL, Snell JD, Stroup SL, Oldham RK. Small cell lung cancer: Complete remission and improved survival. Am J Med 1979;66:625-30. [PUBMED] |
|3.||Aisner J, Whitacre M, Van Echo DA, Wiernik PH. Combination chemotherapy for small cell carcinoma of the lung: Continuous versus alternating non-cross-resistant combinations. Cancer Treat Rep 1982;66:221-30. [PUBMED] |
|4.||Evans WK, Shepherd FA, Feld R, Osoba D, Dang P, Deboer G. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 1985;3:1471-7. [PUBMED] [FULLTEXT]|
|5.||Skarlos DV, Samantas E, Kosmidis P, Fountzilas G, Angelidou M, Palamidas P, et al . Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer: A Hellenic Co-operative Oncology Group study. Ann Oncol 1994;5:601-7. |
|6.||Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, et al . Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992;10:282-91. [PUBMED] [FULLTEXT]|
|7.||Eckardt JR, von Pawel J, Papai Z, Tomova A, Tzekova V, Crofts TE, et al . Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide-cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol 2006;24:2044-51. [PUBMED] [FULLTEXT]|
|8.||Bleehen NM, Girling DJ, Machin D, Stephens RJ. A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC), I: Survival and prognostic factors, Medical Research Council Lung Cancer Working Party. Br J Cancer 1993;68:1150-6. [PUBMED] |
|9.||Giaccone G, Dalesio O, McVie GJ, Kirkpatrick A, Postmus PE, Burghouts JT, et al . Maintenance chemotherapy in small-cell lung cancer:long-term results of a randomized trial: European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1993;11:1230-40. [PUBMED] [FULLTEXT]|
|10.||Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Report to the Medical Research Council by its Lung Murray N, Coy P, Pater JL, et al . Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1993;11:336-44. |
|11.||Thatcher N. Ifosfamide-carboplatin-etoposide (ICE) regimen in small cell lung cancer. Lung Cancer 1993;9:s51-67. |
|12.||Laukkanen E, Klonoff H, Allan B, Graeb D, Murray N. The role of prophylactic brain irradiation in limited stage small cell lung cancer: Clinical, neuropsychologic, and CT sequelae. Int J Radiat Oncol Biol Phys 1988;14:1109-17. [PUBMED] |
|13.||Auperin A, Arriagada R, Pignon JP, Le Pιchoux C, Gregor A, Stephens RJ, et al . Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission: Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476-84. |
|14.||Schiller JH, Adak S, Cella D, DeVore RF 3rd, Johnson DH. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:2114-22. [PUBMED] [FULLTEXT]|
|15.||Jackson DV Jr, Case LD, Zekan PJ, Powell BL, Caldwell RD, Bearden JD, et al . Improvement of long-term survival in extensive small-cell lung cancer. J Clin Oncol 1988;6:1161-9. [PUBMED] [FULLTEXT]|
|16.||Hong WK, Nicaise C, Lawson R, Maroun JA, Comis R, Speer J, et al . Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung:a randomized trial of the Bristol Lung Cancer Study Group. J Clin Oncol 1989;7:450-6. [PUBMED] [FULLTEXT]|
|17.||Glisson BS, Kurie JM, Perez-Soler R, Fox NJ, Murphy WK, Fossella FV, et al . Cisplatin, etoposide, and paclitaxel in the treatment of patients with extensive small-cell lung carcinoma. J Clin Oncol 1999;17:2309-15. |
|18.||Ettinger DS. Evaluation of new drugs in untreated patients with small-cell lung cancer: Its time has come. J Clin Oncol 1990;8:374-7. [PUBMED] [FULLTEXT]|
|19.||Blackstein M, Eisenhauer EA, Wierzbicki R, Yoshida S. Epirubicin in extensive small-cell lung cancer: A phase II study in previously untreated patients: A National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol 1990;8:385-9. [PUBMED] [FULLTEXT]|
|20.||Ettinger DS, Finkelstein DM, Abeloff MD, Skeel RT, Stott PB, Frontiera MS, et al . Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: An Eastern Cooperative Oncology Group randomized study. J Natl Cancer Inst 1992;84:1077-84. [PUBMED] [FULLTEXT]|
|21.||Moore TD, Korn EL. Phase II trial design considerations for small-cell lung cancer. J Natl Cancer Inst 1992;84:150-4. [PUBMED] [FULLTEXT]|
|22.||Ettinger DS, Finkelstein DM, Sarma RP, Johnson DH. Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 1995;13:1430-5. |
|23.||Schiller JH, Kim K, Hutson P, DeVore R, Glick J, Stewart J, et al . Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: An Eastern Cooperative Oncology Group Trial. J Clin Oncol 1996;14:2345-52. [PUBMED] [FULLTEXT]|
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