Twice-daily RT for SCLC

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Turrisi AT, et al. "Twice-Daily Compared with Once-Daily Thoracic Radiotherapy in Limited Small-Cell Lung Cancer Treated Concurrently with Cisplatin and Etoposide". The New England Journal of Medicine. 1999. 340(4):265-271.
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Clinical Question

Among patients with limited-stage small-cell lung cancer (SCLC) receiving standard chemotherapy, how does twice-daily radiotherapy compare to once-daily radiotherapy in terms of overall survival?

Bottom Line

Among patients with limited-stage SCLC receiving standard chemotherapy, twice-daily radiotherapy improves response rate, progression-free survival, and overall survival when compared to once-daily therapy.

Major Points

Concurrent chemoradiation with cisplatin/etoposide is the treatment of choice for limited-stage SCLC, but the optimal dosing strategy of radiotherapy (RT) remains uncertain. Some studies of various fractionation schedules yielded promising results with a twice-daily regimen. The rationale for twice-daily RT hinges on the exponential rate of death of small-cell lung cancer cells when exposed to RT, and the relatively rapid rate of tumor cell repair between RT fractions. Thus, an accelerated twice-daily schedule with a lower radiation dose per fraction may still provide sufficient tumor death, while limiting tumor growth between treatments. However, studies of twice-daily regimens had yielded conflicting results, prompting this follow-up randomized study.

Published in 1999, this study by Turrisi et al. randomized 417 patients with limited-stage SCLC to either twice-daily RT or once-daily radiotherapy. All patients received standard chemotherapy with 4 cycles of cisplatin/etoposide administered every 3 weeks. RT was given concurrently at the start of chemotherapy, with a total dose of 45 Gy. The twice-daily group received RT in 1.5-Gy fractions over a 3-week period; the once-daily group received RT in 1.8-Gy fractions over a 5-week period. At a median follow-up of about 8 years, overall survival was significantly improved in the twice-daily group (23 vs. 19 months). These results were taken to form the NCCN's category 1 statement that 1.5 Gy twice-daily RT over 3 weeks is superior to 1.8 Gy once-daily RT over 5 weeks for limited SCLC.

Notably, these results were not confirmed in a follow-up study by Schild et al. (2004),[1] which demonstrated no difference between twice-daily and once-daily radiation regimens. The major difference between the Turrisi and Schild trials is that the latter investigated a regimen that involved giving two 16-fraction treatments separated by a 2.5-week radiation holiday, whereas radiation was given without a break in the former study. The so-called "split-course" therapy given in the Schild study may have allowed for tumor growth during the 2.5-week break and may have accounted in part for the negative results of the study.[2]

Guidelines

NCCN SCLC (2014, adapted)[2]

  • For limited-stage SCLC, the optimal dose and schedule of RT have not been established.
  • 45 Gy in 3 weeks (1.5 Gy twice daily) is superior to 45 Gy in 5 weeks (1.8 Gy once daily). (Category 1)
  • When twice-daily fractionation is used, there should be at least a 6-hour inter-fraction interval to allow for repair of normal tissue.

Design

  • Multicenter, randomized, comparative trial
  • N=417 patients with limited-stage SCLC
    • Twice-daily RT (n=211)
    • Once-daily RT (n=206)
  • Setting: Unspecified US centers
  • Enrollment: 1989-1992
  • Mean follow-up: ~8 years
  • Analysis: Intention-to-treat
  • Primary outcome: Overall survival

Population

Inclusion Criteria

  • Pathologic diagnosis of small-cell lung cancer (by histology or cytology)
  • Staging by CT or MRI of the chest, abdomen, and brain; nuclear bone scan; bilateral iliac-crest bone marrow aspirate/biopsy
  • Disease confined to one hemithorax, the ipsilateral supraclavicular fossa, or both
  • Adequate organ reserve: WBC >4, PLT >100k, Cr <1.5 mg/dl, AST and ALT < 2xULN, Tbili < 0.5mg/dl, FEV1 >1.0L
  • Available for follow-up

Exclusion Criteria

  • Pleural effusion on chest film (regardless of cytology)
  • Contralateral hilar/supraclavicular lymphadenopathy
  • Symptomatic cardiac disease or MI within prior 6 months
  • Other prior cancer
  • Prior treatment with chemo- or radiotherapy

Baseline Characteristics

From the once-daily group.

  • Mean age: 63 years
  • Male: 59%
  • White 90%
  • ECOG PS: 0 (43%), 1 (51%), 2 (5%)
  • Disease site:
    • Ipsilateral lung: 49%
    • Mediastinum: 59%
    • Ipsilateral supraclavicular: 3%

Interventions

  • Randomized to a group:
    • Once-daily RT - 45 Gy total, 1.8 Gy once daily in 25 fractions over 5 weeks
    • Twice-daily RT - 45 Gy total, 1.5 Gy twice daily in 30 fractions over 3 weeks
  • All patients received standard chemotherapy every 3 weeks for a total of 4 cycles:
    • Cisplatin 60mg/m2 on day 1
    • Etoposide 120mg/m2 on days 1, 2, and 3
    • No dose adjustments during first 2 cycles
  • Restaging imaging after 12 weeks with CXR, CT head, CT chest:
    • Individuals with a complete response were offered prophylactic cranial irradiation (25 Gy total, 2.5 Gy daily in 10 fractions over 2 weeks)
  • Dose adjustments:
    • Radiation held for platelet count <50k, weight loss ≥4.5kg (Grade 2), or hospitalization for neutropenic fever or sepsis
    • During cycles 3 and 4, etoposide reduced for grade 4 toxicity, febrile neutropenia, infection, or thrombocytopenia with bleeding
    • During cycles 3 and 4, cisplatin was reduced for Cr 1.6-2.5 mg/dl and further reduced for Cr ≥2.6 mg/dl
  • Response measurement:
    • CR: disappearing of all clinical evidence of tumor
    • PR: decrease of ≥50% in the product of length and width, for ≥4 weeks
    • PD: ≥10% weight loss, ≥25% increase in diameter of a ≥2cm tumor, or ≥50% increase in diameter of a <2cm tumor, or new tumor

Outcomes

Comparisons are twice-daily vs. once-daily RT.

Primary Outcome

Overall survival
23 vs. 19 months (P=0.04)

Secondary Outcomes

Two-year survival
47% vs. 41%
Five-year survival
26% vs. 16% (P=0.04)
Complete response
56% vs. 49%
Partial response
31% vs. 38%
Overall response rate
87%
Stable disease
4%
Progressive disease
6% vs. 8%

Subgroup Analysis

In a prespecified subgroup analysis, male sex and ECOG PS 2 were associated with decreased disease-free survival.

Adverse Events

Any grade ≥3 toxicity
90% vs. 88% (P=NS)
Grade ≥3 myelotoxicity
87% vs. 85.5% (P=NS)
Defined as any decrease in marrow-derived peripheral blood counts
Grade ≥3 esophagitis
32% vs. 16% (P<0.001)
Other grade ≥3 toxicity
35% vs. 31% (P=NS)

Criticisms

  • The control group used approximately 50% of total Gy dose that is considered curative by many radiation oncologists[3].
    • This has led to a currently open phase III trial to investigate BID vs high dose radiation, CALGB-30610
  • Fewer patients ≥65 years old (31% vs. 40%) may have led to more favorable outcomes in the twice-daily group
  • High rate of grade 3 esophagitis indicates that tolerability of the treatment is low[3]
  • Limited details about the planning for dose administration and the amount of participants receiving prophylactic whole-brain radiation[3]

Funding

Funded by the NCI, NIH, and DHHS.

Further Reading

  1. Schild SE, et al. "Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer." Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):943-51.
  2. 2.0 2.1 NCCN Small-cell lung cancer guidelines (2.2014)
  3. 3.0 3.1 3.2 Multiple authors. "Correspondence: "Radiotherapy for small-cell lung cancer." The New England Journal of Medicine. 1999;340;2002-2004.