Small-cell lung cancer (SCLC) accounts for approximately 15% of the nearly 170,000 lung cancers diagnosed in the United States annually. Nearly one third of these are categorized as limited-stage (LS) based on their clinical confinement to a single hemithorax and regional lymph nodes, and the ability to treat in a reasonable radiation field. Because the majority of patients have occult metastatic disease, chemotherapy remains the primary modality of therapy.   However, in recent years the role of thoracic radiation therapy (TRT) has garnered a great deal of attention. During the 1970s and 1980s, numerous studies were conducted to assess whether the addition of TRT to chemotherapy in the treatment of LS-SCLC was beneficial. Although many of these studies suggested a benefit in both local control and overall survival, most did not show a statistically significant benefit with the addition of TRT. Meta-analyses by Pignon were conducted to help clarify this issue. Both found a modest but significant increase in survival in the combined-therapy group. Warde  also found a major decrement in thoracic recurrence in the combined group relative to the chemotherapy-alone group.

Although TRT is generally accepted as an integral part of the treatment of LS-SCLC, controversy remains regarding its dose, fractionation, and timing. In their meta-analysis, Pignon  attempted to assess the impact of TRT timing (early v late and concurrent v sequential or alternating) on overall survival, but were able only to make indirect comparisons between studies. They did not find any statistically significant differences in the timing of TRT relative to chemotherapy. More recently, several studies have been conducted with the primary intent of examining the effect of the timing of TRT on survival in LS-SCLC. Early studies of this topic, as well as those included in the aforementioned meta-analyses, used combination chemotherapy typically consisting of cyclophosphamide, doxorubicin, and vincristine. In more recent studies, these agents have largely been replaced by platinum-based regimens (either cisplatin or carboplatin) and etoposide. A meta-analytic review addressing the timing of TRT was conducted by Cancer Care of Ontario in 1999 and updated in 2003. In this review no difference was found in a comparison of early versus late TRT. However, this study has not been published in a peer-reviewed journal and does not include the more recent peer-reviewed published data on this subject. In addition, it includes data from trials that have only been published in abstract form, as well as those published as articles in peer-reviewed journals.

Controversy also exists regarding the optimal TRT fractionation scheme in the treatment of LS-SCLC. Twice-daily fractionation is theoretically advantageous for malignancies such as SCLC that are characterized by rapid cell proliferation. Two trials have been conducted specifically to assess the effect of hyperfractionation in LS-SCLC. Turrisi  reported on a randomized trial of concurrent chemoradiotherapy with radiation dose to 45 Gy delivered either twice daily (hyperfractionated) or once daily with the first cycle of cisplatin and etoposide. A statistically significant increase in 2- and 5-year overall survival (OS) rates was found for the hyperfractionated arm. In contrast, Bonner  conducted a similar study; however, the TRT was delayed until the start of the fourth cycle of cisplatin and etoposide, and those patients randomly assigned to hyperfractionated radiation were given a midcourse break of 2.5 weeks. No benefit in OS was observed with the use of twice-daily radiation. These findings suggest that the potential benefit of hyperfractionation is counterbalanced by the delay of using a split course of therapy in the twice-daily arm.

To try to address the issues of chemotherapy regimen and fractionation scheme in relation to the timing of radiation, we performed a meta-analysis evaluating early versus late timing of radiation therapy (ERT v LRT, respectively) in LS-SCLC. In addition, using subgroup analyses and meta-regression analyses, we evaluated the impact of radiation fractionation and chemotherapeutic regimens on the timing of TRT.

PURPOSE: We employed meta-analytic techniques to evaluate early (E) versus late (L) timing of thoracic radiation therapy (RT) in limited-stage small-cell lung cancer (LS-SCLC). In addition, we assessed the impact of radiation fractionation and chemotherapeutic regimen on timing.

METHODS: Randomized trials published after 1985 addressing timing of RT relative to chemotherapy in LS-SCLC were included. Trials were analyzed by risk ratio (RR), risk difference, and number-needed-to-treat methods.

Definitions
ERT was defined as beginning before 9 weeks after the initiation of chemotherapy and before the third cycle of chemotherapy. LRT was defined as beginning 9 weeks or more after the initiation of chemotherapy or after the beginning of the third cycle of chemotherapy.

RESULTS: Overall survival (OS) RRs for all studies were 1.17 at 2 years and 1.13 at 3 years indicating a significantly increased 2-year survival for ERT versus LRT patients and suggestive of a similar trend at 3 years. Subset analysis of studies using hyperfractionated RT revealed OS RR for ERT versus LRT of 1.44  and 1.39  at 2 and 3 years, respectively, indicating a survival benefit of ERT versus LRT. Studies using once-daily fractionation showed no difference in 2- and 3-year OS RRs for ERT compared with LRT. Studies using platinum-based chemotherapy had OS RRs of 1.30  and 1.35  at 2 and 3 years, respectively, favoring ERT. Studies using nonplatinum-based chemotherapy regimens had nonsignificant differences in OS.

CONCLUSION: A small but significant improvement in 2-year OS for ERT versus LRT in LS-SCLC was observed, similar to the benefit of adding RT to chemotherapy or prophylactic cranial irradiation. A greater difference was evident for hyperfractionated RT and platinum-based chemotherapy.