Cooperative Group Research Endeavors in Small-cell Lung Cancer: Current and Future Directions

Current and Future Directions

Randeep Sangha; Primo N. Lara, Jr.; Alex A. Adjei; Paul Baas; Hak Choy; Laurie E. Gaspar; Glenwood Goss; Nagahiro Saijo; Joan H. Schiller; Everett E. Vokes; David R. Gandara

Disclosures

Clin Lung Cancer. 2009;10(5) 

In This Article

Cancer and Leukemia Group B

In 1987, the CALGB published a seminal report (CALGB 8083) describing the benefits of thoracic irradiation when given concurrently with chemotherapy for patients with LS-SCLC.[14] Improvements in local control, failure-free survival, and OS strengthened the case for shifting the standard of care to a chemoradiation therapy approach. Unfortunately, in 2009, many questions still remain unanswered regarding the optimal dose and delivery of thoracic irradiation.

Cancer and Leukemia Group B has been instrumental in exploring the 70-Gy maximum-tolerated dose (MTD) of once-daily radiation therapy in a phase II setting.[13,15] For example, CALGB conducted CALGB 39808, in which 57 patients with LS-SCLC were treated with 70 Gy in 35 once-daily fractions concurrently with carboplatin/etoposide following 2 cycles of induction paclitaxel and topotecan.[16] The reported 2-year survival was 48%, and the incidence of grade 3 dysphagia was 16%. However, the experience with 70 Gy of concurrent thoracic chemoradiation remains limited and, as a consequence, the de facto practice still calls for once-daily radiation therapy to be delivered at a total dose of 50–60 Gy in 1.8–2.0–Gy fractions.

Hyperfractionating radiation therapy is believed to offer additional clinical benefits. An Intergroup 0096 phase II trial randomized 417 patients to receive 4 cycles of cisplatin/etoposide with either 45 Gy of concurrent thoracic irradiation given twice daily over 3 weeks or once-daily for 5 weeks. Thoracic irradiation was scheduled to coincide with the start of chemotherapy. This pivotal trial found a significant 5-year OS benefit favoring twice-daily thoracic irradiation compared with once-daily fractionation (26% vs. 16%; P = .04) and a lower incidence of local failure (36% vs. 52%; P = .06).[9] Grade 3 esophagitis was the most significant toxicity with twice-daily radiation therapy (26% twice-daily vs. 11% once-daily), but the incidence of grade 4 esophagitis did not differ between regimens.

Radiation Therapy Oncology Group has examined an alternative fractionation scheme using a concomitant boost technique to escalate dose while keeping the total treatment duration at 5 weeks. Initially, thoracic irradiation is administered once-daily for 3 weeks, followed by 2 weeks of twice-daily thoracic irradiation. This dose/fractionation regimen is hypothesized to counteract accelerated repopulation, the increased tumor cell growth rate that is known to often occur several weeks into treatment. The MTD for the concomitant-boost technique, when combined with cisplatin/etoposide chemotherapy, has been determined at 61.2 Gy.[17] Thus, there are 3 plausible treatment regimens for delivering concurrent thoracic radiation therapy in LS-SCLC at relatively similar biologically effective doses: (1) CALGB's 70-Gy once-daily fractionation for 7 weeks, (2) the Intergroup 0096 regimen of 45-Gy twice-daily fractionation for 3 weeks, and (3) RTOG's 61.2-Gy concomitantboost technique for 5 weeks duration.

To address the important radiation therapy questions of optimal dose and fractionation schemes, CALGB 30610, an Intergroup study, has now been developed (Figure 1). This pivotal phase III trial for patients with treatment-naive LS-SCLC is the first of its kind in well over a decade. It consists of 2 parts; part 1 has 3 treatment arms with patients randomized in a 1:2:2 fashion: arm A, 45 Gy (1.5 Gy twice daily × 3 weeks); arm B, 70 Gy (2.0 Gy once daily × 7 weeks); arm C, 61.2 Gy (1.8 Gy once daily × 16 days followed by 1.8 Gy twice daily × 9 days for a total duration of 5 weeks). Four cycles of cisplatin and etoposide are given concurrently, starting on day 1 of radiation therapy for all arms of this study. After interim analysis for toxicity assessment, only 1 experimental arm (arm B or arm C) will be selected for further accrual in part 2 of the study. The primary endpoint will be OS, and the projected total accrual is approximately 712 patients.

Figure 1.

CALGB 30610/RTOG 0538 Treatment Schema: Phase III Trial Comparing Thoracic Radiation Therapy Regimens in Limited-Stage Small-Cell Lung Cancer
Abbreviations: 3D = 3-dimensional conformal radiation therapy; b.i.d. = twice daily; CALGB = Cancer and Leukemia Group B; CB = concomitant boost; ECOG = Eastern Cooperative Oncology Group; FFS = failure-free survival; fr = fractions; IMRT = intensity-modulated radiation therapy; LN = lymph node; LS-SCLC = limited-stage small-cell lung cancer; OS = overall survival; PS = performance status; RR = response rate; RTOG = Radiation Therapy Oncology Group; TRT = thoracic radiation therapy

Several randomized trials have attempted to build on the platform of platinum/etoposide chemotherapy for ES-SCLC; however, these attempts have been met with disappointing results. For example, the addition of topotecan consolidation, paclitaxel, BEC2 vaccination, or thalidomide to the platinum/etoposide backbone have not shown any significant survival advantage.[18–22] Furthermore, CALGB 30103, a randomized phase II trial, evaluated the Bcl-2 antisense oligonucleotide, oblimersen (G3139), in combination with carboplatin/etoposide in 56 chemotherapy-naive patients with ES-SCLC. Although Bcl-2 is an overexpressed apoptotic inhibitor implicated in SCLC oncogenesis and chemotherapy resistance, CALGB 30103 suggested poorer clinical outcomes for patients who received oblimersen than for those who did not (1-year OS rates, 24% and 47%).[23]

Sunitinib, an oral small-molecule, multitargeted receptor tyrosine kinase inhibitor, has been FDA approved for the treatment of patients with renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. It has potent inhibitory effects of the platelet-derived growth factor receptors (PDGFRs)-α and -β, vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT-3), colony stimulating factor receptor (CSF)-1R, and the glial cell line–derived neurotrophic factor receptor (RET). Given its promiscuity in inhibition, sunitinib is hypothesized to affect multiple hallmarks of cancer, including angiogenesis and tumor cell proliferation. CALGB 30504 is an ongoing phase I/II clinical trial investigating the combination of sunitinib plus cisplatin/etoposide for patients with ES-SCLC. The phase I portion of the trial will determine the MTD to be used for the phase II portion. Sunitinib will be given daily concurrent with 6 cycles of cisplatin/etoposide, followed by maintenance sunitinib until the development of progressive disease (PD) or excessive toxicity. The phase II portion of the trial will randomize patients, after initial treatment with sunitinib plus cisplatin/etoposide, to maintenance therapy with either sunitinib or placebo. The primary endpoint will be progression-free survival (PFS), with an accrual goal of 107 patients.

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