Although the standard treatment regimen for limited stage small cell lung cancer (SCLC) has not appreciably changed in the past 30 years, this entity continues to generate major interest in the radiation oncology community. Although it is far less common than non-small cell lung cancer, there are still more than 30,000 patients diagnosed with SCLC in the US annually, approximately a third with limited stage disease. Historically, limited SCLC is one of the few disease entities where randomized clinical trials have demonstrated that integrating and optimizing radiotherapy may ultimately result in improved overall survival.
SCLC is considered a systemic disease at diagnosis even in the absence of documented extra-thoracic metastases, given its propensity to metastasize early; systemic chemotherapy has been the mainstay of treatment. The addition of thoracic radiotherapy to chemotherapy in limited disease was shown to improve overall survival in metanalyses published in the early 1990s.1,2,3 The standard radiotherapy regimen, 1.5 Gy twice-daily to 45 Gy over 3 weeks, was defined by the Intergroup trial 0096 (INT-0096), a phase III study completed in 1992. Accelerating radiotherapy from 45 Gy once-daily for 5 weeks to 45 Gy twice-daily for 3 weeks, with 4 cycles of cisplatin and etoposide chemotherapy, resulted in a significant improvement in 5-year overall survival (OS) from 16% to 26%.4 The main drawback of the twice-daily regimen was the doubling of acute severe esophagitis from 16% to 32%.
Despite the impact of twice-daily radiotherapy on survival in INT-0096, adoption of the twice-daily regimen has been muted. Most patients receive once-daily treatment in practice.5 Reasons why twice-daily has not been routinely adopted as standard practice include concerns regarding the higher rate of acute esophagitis, logistical challenges in scheduling treatment, and patient preferences, with many finding it difficult to attend twice-daily treatments that need to be separated by at least 6 hours. Perhaps the most impactful rationale articulated was the relatively low total radiotherapy dose used in the once-daily arm of INT-0096, which contrasts with the 60 Gy in once-daily fractions of 2 Gy, which now is the standard of care for concurrent chemoradiotherapy in NSCLC.
When the INT-0096 trial was conducted, modest total doses of radiotherapy were used in part because small cell was considered a radiosensitive disease; in addition, dose escalation was limited by the available technology of the time. Radiotherapy planning and delivery techniques have markedly advanced during the past decades, resulting in many centers routinely delivering higher doses of once-daily radiotherapy.
The rationale for delivering higher daily doses with more conformal radiotherapy techniques was the assumption that higher doses were both safe and effective. Prospective trials conducted by the Cancer and Leukemia Group B (CALGB) suggested that it was feasible to raise radiotherapy dose with standard fractionation to 70 Gy or higher.6 In particular, the CALGB 39808 phase II study suggested that high dose, once daily radiotherapy might yield efficacy comparable to the 45 Gy twice-daily regimen. Interest in studying high dose daily RT, coupled with the reluctance for many centers to adopt twice-daily radiotherapy, led to the design of two large phase III trials testing whether high-dose, once-daily treatment could improve overall survival compared with “standard” 45 Gy twice-daily treatment. The CONVERT study, conducted in the UK and Canada, assigned patients with limited-stage disease to receive either 66 Gy once-daily radiotherapy or 45-Gy twice-daily radiotherapy.7 Outcomes were not improved in the 66 once-daily cohort; in fact, median survival seemed to favor the 45 Gy twice-daily group (30 vs. 25 months), though the difference was not significant (HR, 1.18; P =.14).
The CALGB 30610/RTOG 0534 phase 3 study employed the 70 Gy regimen in the once-daily arm, and also initiated with an experimental concomitant boost regimen that had been piloted by the Radiation Therapy Oncology Group (RTOG).8 The trial design mandated discontinuing one of the experimental arms based on early interim analysis; consequently, the 70 Gy arm was selected to continue in comparison to the “standard” 45 Gy twice-daily arm. Outcomes on the high-dose, once-daily arm once again did not prove superior to standard therapy, though the results appeared more numerically comparable. After a median follow-up of almost 5 years, median OS was 28.5 months (95% CI, 25.4 to 34.5) for 45-Gy twice-daily compared with 30.1 months (95% CI, 24.4 to 37.2) for 70-Gy once-daily radiotherapy (p=0.594). 5-year OS were 29% (95% CI, 0.24 to 0.35) on the 45-Gy arm, compared to 33% (95% CI, 0.28 to 0.39) on the 70-Gy arm.
In contrast to the INT-0096 trial, the toxicity profiles of twice-daily and once-daily radiotherapy were generally similar on both the CONVERT and CALGB trials. For example, on the CALGB trial, grade 3 esophageal toxicity was 16% in the 45-Gy twice-daily arm and 17.5% in the 70-Gy once-daily arm. The lower rates of esophageal toxicity compared to that documented previously with twice-daily radiotherapy was attributed to both improved technology and to the delineation of smaller treatment volumes given that treatment of uninvolved mediastinal lymph nodes was no longer considered standard. Rates of select hematologic toxicities were higher with once-daily radiotherapy on both trials, though the clinical relevance of toxicities such as leukopenia and lymphopenia are not apparent.
The final interpretation of CONVERT and CALGB 30610 and the impact on clinical practice remains to be seen. The recently completed NRG LU-005 trial (NCT03811002) testing the addition of atezolizumab for patients with limited stage disease, was designed after CONVERT results had been reported. The trial allowed investigator choice of radiotherapy regimen, either 66 Gy once -daily or 45 Gy twice-daily. While most patients were treated with once-daily RT, more than 40% received twice-daily RT. In comparison, surveys prior to the CONVERT trial suggested fewer than 20 % of patients outside of clinical trials received twice-daily radiotherapy.4
These trials do not provide certainty regarding the optimal thoracic radiotherapy regimen; thus, for many, 45 Gy twice-daily remains the de facto standard of care while the option of high dose once-daily radiotherapy is included in most guidelines. Certain issues may be considered by physicians and patients in deciding on treatment regimen. Some factors may favor consideration of the 45 Gy twice-daily regimen, particularly the observation that patients on the twice-daily arm of both trials were more likely to complete the prescribed course of radiotherapy.
Some measures of hematologic toxicity were lower on the twice-daily arm in both trials, and while the clinical relevance is not clear, these toxicities could become impactful if novel agents such as checkpoint inhibitors become standard. While severe non-hematologic acute toxicities were similar, a subset analysis of the CONVERT trial noted increased esophagitis with twice-daily treatment for N3 disease.
Convenience has been a major issue cited in the low uptake of twice-daily RT. While the once-daily regimen was deemed slightly more convenient by patients in the CALGB study, the overall social and financial impact, including the need to travel and the cost of missing work, will likely vary according to specific patient circumstances. Some patients prefer completing therapy quickly even if it means coming twice a day, particularly if the center is able to provide resources such as guest housing, while others may have outside responsibilities that preclude the ability to come for treatment twice daily. There remains considerable uncertainty regarding the optimal dose of once-daily radiotherapy. While the American Society for Therapeutic Radiation and Oncology guidelines suggest using doses between 60 and 70 Gy, the level of evidence is low, and an overall review of prospective trials does not establish a clear relationship between dose and overall survival.9 Recently, the optimal dose of twice-daily radiotherapy has also been questioned. Provocative outcomes from a randomized phase II trial in Scandinavia comparing 60 Gy twice-daily to 45 Gy twice-daily with median survival of 37.2 months on the 60 Gy arm, have resulted in 60 Gy twice-daily radiotherapy being adopted as standard of care in Norway and Sweden.10 At this time there has been limited experience with 60 Gy twice-daily radiotherapy in North America, though a phase II trial exploring this regimen is planned by the Alliance for Clinical Trials in Oncology and NRG.
References
- 1. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med. 1992 Dec 3;327(23):1618-24.
- 2.
- 3. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol. 1992 Jun; 10(6):890-5.
- 4. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 Jan 28;340(4):265-71.
- 5. Farrell MJ, Yahya JB, Degnin C, et al. Radiation Dose and Fractionation for Limited-stage Small-cell Lung Cancer: Survey of US Radiation Oncologists on Practice Patterns. Clin Lung Cancer. 2019 Jan;20(1):13-19.
- 6. Bogart JA, Herndon JE 2nd, Lyss AP, et al. Cancer and Leukemia Group B study 39808. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):460-8
- 7. Faivre-Finn C, Snee M, Ashcroft L, et al. CONVERT Study Team. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017 Aug;18(8):1116-1125.
- 8. Bogart J, Wang X, Masters G, et al. High-Dose Once-Daily Thoracic Radiotherapy in Limited-Stage Small-Cell Lung Cancer: CALGB 30610 (Alliance)/RTOG 0538. J Clin Oncol. 2023 May 1;41(13):2394-2402.
- 9. Simone CB 2nd, Bogart JA, Cabrera AR, et al. Radiation Therapy for Small Cell Lung Cancer: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol. 2020 May-Jun;10(3):158-173.
- 10. Grønberg BH, Killingberg KT, Fløtten Ø, et al. High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial. Lancet Oncol. 2021 Mar;22(3):321-331.
