In the current climate of rising health-care costs, particularly in the field of oncology, clinical guidelines provide a crucial tool to guide practitioners in evidence-based care and to improve the quality and consistency of care.1 The ASCO review and endorsement of the American College of Chest Physicians (ACCP) guidelines on small cell lung cancer (SCLC)—recently reported by Rudin and colleagues2 and summarized in this issue of The ASCO Post—provide an important addition to the consistent message conveyed by both the ACCP guidelines and National Comprehensive Cancer Network (NCCN) guidelines on the management of SCLC.
Key Affirmations
The ASCO review, led by Drs Giaccone and Rudin, endorses consideration of surgery as the modality of local therapy for stage I tumors, provided there has been rigorous clinical and pathologic staging. For these patients, as well as patients with limited-stage disease and tumors more extensive than stage I, positron-emission tomography–computed tomography (PET-CT) is recommended to exclude distant metastases. The ASCO review extended this recommendation to the staging evaluation of patients with extensive-stage disease, noting that if PET-CT is performed, a bone scan may be omitted. The use of PET-CT has also thankfully allowed for the removal of invasive bone marrow biopsy as part of staging.3
The ASCO panel also endorsed longstanding recommendations to treat elderly patients with good performance status equivalently to younger patients, with platinum-based chemotherapy and with the addition of thoracic radiation therapy in patients with limited-stage disease. In addition, the ASCO panel affirmed the goal of treating even poor–performance status patients with chemotherapy if the poor performance status is deemed to be due to cancer.
Key Modifications
The ASCO panel also made several qualifying statements to the ACCP recommendations that modified the endorsement of particular points. Specifically, although the ACCP recommended twice-daily hyperfractionated radiation therapy as the standard for limited-stage patients (when given concurrently with chemotherapy), the ASCO review notes that there is an ongoing Radiation Therapy Oncology Group/Cancer and Leukemia Group B study comparing twice-daily hyperfractionated radiotherapy (45 Gy or 70 Gy) to a higher total dose of once-daily radiotherapy (70 Gy). This qualifier is more reflective of real-world practice, where logistics of administration often limit the use of hyperfractionated therapy.
The ASCO review also emphasizes the point that trials in the United States and Europe have not shown superiority of irinotecan over etoposide as a partner in platinum-doublet chemotherapy and that platinum plus etoposide remains the standard of care in the United States for first-line treatment of both limited- and extensive-stage disease.
With regard to systemic therapy in the second line, the ACCP focuses on retreatment with the original regimen (only beneficial with a disease-free interval of > 6 months) or irinotecan. The ASCO review emphasizes that topotecan is the only approved second-line agent that has randomized data showing benefit. Although amrubicin is approved in the second-line setting in Japan, it is not approved in the United States due to failure to show improvement in overall survival despite improved response rate when compared to topotecan.4
Areas of Controversy
One of the most important aspects of guidelines is that they provide up-to-date assessments of the field to make recommendations. In many tumor types, this can mean rapidly changing guidelines with the advent of new drug approvals, which are happening more and more quickly in oncology. In SCLC, the major advances have come not from changes in systemic therapy but in radiotherapy.
Although the ASCO review of the ACCP guidelines was released in 2015, the ACCP guidelines themselves were published in 2013.5 Since 2013, two important trials of radiotherapy were completed and presented at the 2014 ASCO meeting. The most recent of them, from Slotman and colleagues, was a randomized phase III trial of consolidation thoracic radiation therapy in patients with extensive-stage SCLC who had a good response in extrathoracic disease. This study demonstrated improved progression-free survival and significantly improved 2-year overall survival with the addition of thoracic radiation, although the primary endpoint of improved 1-year survival was not met for unclear reasons.6
This study underscored similar findings from a randomized phase II study by Jeremic and colleagues from 1999.7 The ACCP recommended consideration of consolidation thoracic radiation based on the Jeremic et al study alone; however, although the ASCO review panel had data from the second randomized phase III study, they declined to make a recommendation, saying further study is required. The NCCN panel has also recommended cautious consideration of thoracic radiation in selected patients based on both of the above-mentioned studies, as well as a third, nonrandomized study suggesting benefit.8
Another area of treatment that remains controversial is the use of prophylactic cranial irradiation following treatment of either limited- or extensive-stage SCLC. Meta-analyses in 1999 and 2009 established the survival benefit of prophylactic cranial irradiation for limited-stage SCLC,9,10 but a randomized study from Slotman and colleagues in extensive-stage SCLC led to the widespread adoption of prophylactic cranial irradiation in patients who had a response to chemotherapy, regardless of stage.11
However, the Slotman study was flawed in an important way. No magnetic resonance imaging (MRI) scans were performed prior to randomization to prophylactic cranial irradiation or no prophylactic cranial irradiation—therefore, it is likely that there were at least some patients with asymptomatic brain metastases in the patient population who contributed to the benefit seen with “prophylactic cranial irradiation” (not really prophylactic in these cases).
A similar study from Seto and colleagues in Japan was presented at the 2014 ASCO Annual Meeting; in this study’s design, all patients underwent screening MRI to determine CNS disease-free status prior to randomization.12 In addition, patients who were not randomized to prophylactic cranial irradiation were followed with serial MRI. In this study, there was no survival benefit seen with the prophylactic technique.
Given the morbidity (cognitive and other neurotoxicity) seen with prophylactic cranial irradiation, this study has led to a more cautious approach in recommending the strategy at many centers, including our own. However, although guidelines in Japan were changed after this presentation, the study has not actually been published yet and thus has not yet changed guidelines elsewhere. However, the ASCO review does modify the ACCP recommendation for prophylactic cranial irradiation in noting that publication of the Japanese study may lead to revision of that recommendation.
Future Outlook
With the advent of immunotherapy showing promise in multiple tumor types including SCLC and with promising data from PARP inhibitors and other novel agents leading to more clinical trials, future guidelines will hopefully incorporate new systemic therapy options as well. SCLC still is largely a systemic problem that is in dire need of improved systemic strategies in addition to improved staging and radiation approaches. ■
Disclosure: Dr.Gandhi reported no potential conflicts of interest.
References
1. Grimshaw JM, Russell IT: Effect of clinical guidelines on medical practice: A systematic review of rigorous evaluations. Lancet 342:1317-1322, 1993.
2. Rudin CM, Ismaila N, Hann CL, et al: Treatment of small-cell lung cancer: American Society of Clinical Oncology endorsement of the American College of Chest Physicians guideline. J Clin Oncol 33:4106-4111, 2015.
3. Fischer BM, Mortensen J, Langer SW, et al: A prospective study of PET/CT in initial staging of small-cell lung cancer: Comparison with CT, bone scintigraphy and bone marrow analysis. Ann Oncol 18:338-345, 2007.
4. von Pawel J, Jotte R, Spigel DR, et al: Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol 32:4012-4019, 2014.
5. Jett JR, Schild SE, Kesler KA, et al: Treatment of small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed—American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143(suppl):e400S-e400s-e419S, 2013.
6. Slotman BJ, van Tinteren H, Praag JO, et al: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: A phase 3 randomised controlled trial. Lancet 385:36-42, 2015.
7. Jeremic B, Shibamoto Y, Nikolic N, et al: Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study. J Clin Oncol 17:2092-2099, 1999.
8. Yee D, Butts C, Reiman A, et al: Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 102:234-238, 2012.
9. Auperin A, Arriagada R, Pignon JP, 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 341:476-484, 1999.
10. Patel S, Macdonald OK, Suntharalingam M: Evaluation of the use of prophylactic cranial irradiation in small cell lung cancer. Cancer 115:842-850, 2009.
11. Slotman BJ, Mauer ME, Bottomley A, et al: Prophylactic cranial irradiation in extensive disease small-cell lung cancer: Short-term health-related quality of life and patient reported symptoms: Results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol 27:78-84, 2009.
12. Seto T, Takahashi T, Yamanaka T, et al: Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial. 2014 ASCO Annual Meeting. Abstract 7503.
Dr. Gandhi is a medical oncologist at the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston.
