The patient undergoes FDG PET scan, which shows the presence of a hypermetabolic right hilar mass in addition to enlarged and hypermetabolic bilateral mediastinal lymph nodes. There are no other areas of FDG avidity. Brain MRI does not show any evidence of brain metastasis. Thus, the patient is confirmed to have limited-stage SCLC.
• What is the standard of care treatment for limited-stage SCLC?
SCLC is exquisitely sensitive to both chemotherapy and radiation, especially at the time of initial presentation. The standard of care treatment of limited-stage SCLC is 4 cycles of platinum-based chemotherapy in combination with thoracic radiation started within the first 2 cycles of chemotherapy (Figure 1).
This regimen yields an overall response rate between 75% and 90% and a complete response rate of 50%, with a median OS of 18 to 24 months.13 The cure rate with this approach is approximately 25%, with the remaining 75% of patients experiencing disease relapse within the first 5 years after completion of treatment. Attempts to improve the cure rate in the limited-stage setting by combining standard of care therapies with novel agents have been unsuccessful.
CHOICE OF CHEMOTHERAPY
Etoposide and cisplatin is the most commonly used initial combination chemotherapy regimen in limited-stage SCLC.14 This combination has largely replaced anthracycline-based regimens given its favorable efficacy and toxicity profile.15–17 Several small randomized trials have shown comparable efficacy of carboplatin and etoposide in extensive-stage SCLC.18–20 A meta-analysis of 4 randomized trials comparing cisplatin-based versus carboplatin-based regimens in 663 patients with SCLC (32% had limited-stage disease and 68% had extensive-stage disease) showed no statistically significant difference in response rate, progression-free survival (PFS), or OS between the 2 regimens.21 Therefore, in clinical practice carboplatin is frequently used instead of cisplatin in patients with extensive-stage disease. In patients with limited-stage disease, cisplatin is still the drug of choice. However, the toxicity profile of the 2 regimens is different. Cisplatin-based regimens are more commonly associated with neuropathy, nephrotoxicity, and chemotherapy-induced nausea/vomiting,18 while carboplatin-based regimens are more myelosuppressive.22 In addition, the combination of thoracic radiation with either of these regimens is associated with a higher risk of esophagitis, pneumonitis, and myelosuppression.23 The use of myeloid growth factors is not recommended in patients undergoing concurrent chemoradiation.24 Of note, intravenous etoposide is always preferred over oral etoposide, especially in the curative setting given the unreliable absorption and bioavailability of oral formulations.
THORACIC RADIOTHERAPY
Adding thoracic radiotherapy to platinum-etoposide chemotherapy improves local control and OS. Two meta-analyses of 13 trials including more than 2000 patients have shown a 25% to 30% decrease in local failure and a 5% to 7% increase in 2-year OS with chemoradiation compared to chemotherapy alone in limited-stage SCLC.25,26 Early (within the first 2 cycles) concurrent thoracic radiation is superior to delayed and/or sequential radiation in terms of local control and OS.23,27,28 The dose and fractionation of thoracic radiation in limited-stage SCLC has remained a controversial issue. The Eastern Cooperative Oncology Group/Radiation Therapy Oncology Group randomized trial compared 45 Gy of radiotherapy delivered twice daily over a period of 3 weeks to 45 Gy once daily over 5 weeks concurrently with chemotherapy. The twice daily regimen led to a 10% improvement in 5-year OS (26% versus 16%), but a higher incidence of grade 3 and 4 adverse events.13 Despite the survival advantage demonstrated by hyperfractionated radiotherapy, the results need to be interpreted with caution because the radiation doses are not biologically equivalent. In addition, the difficult logistics of patients receiving radiation twice a day has limited the routine implementation of this strategy. Subsequently, another randomized phase 3 trial (CONVERT) compared 45 Gy radiotherapy twice daily with 66 Gy radiotherapy once daily in limited-stage SCLC.29 This trial did not show any difference in OS. The patients in the twice daily arm had a higher incidence of grade 4 neutropenia. Considering the results of these trials, both strategies—45 Gy fractionated twice daily or 60 Gy fractionated once daily, delivered concurrently with chemotherapy—are acceptable in the setting of limited-stage SCLC. However, quite often a hyperfractionated regimen is not feasible for patients and many radiation oncology centers. Hopefully, the ongoing CALGB 30610 study will clarify the optimal radiation schedule for limited-stage disease.
